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Cited by 118Cancer Immunotherapy and Biomarkersinterferon and immune responsesIntraperitoneal and Appendiceal Malignancies

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STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer

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Lee, Seung Joon, Yang, Hannah, Kim, Woo Ram, Lee, Yu Seong, Lee, Won Suk, Kong, So Jung, Lee, Hye Jin, Kim, Jeong Hun, Cheon, Jaekyung, Kang, Beodeul, Chon, Hong Jae, Kim, Chan·2021·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2020-002195PMC PMC8215239
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Abstract

Background: Peritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway. Methods: We generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling. Results: Intraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8 + T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity. Conclusions: STING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.

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Figure 1 Intraperitoneal colon cancer cells established a highly angiogenic and immunosuppressive milieu within the peritoneal cavity. Mice were intraperitoneally implanted with MC38 colon cancer cells and temporal changes were serially analyzed. (A) Schematic diagram depicting the experimental schedule. (B) Representative images and comparisons of peritoneal tumors. (C) Representative images and comparisons of the peritoneal tumor blood vessels. (D) Representative images and comparisons of malignant ascites over time. (E, F) Representative images and comparisons of CD31+ blood vessels (E), and CD11b+ F4/80+ tumor-associated macrophages (TAMs), CD206+ M2-like macrophages, and iNOS+ M1-like macrophages (F). (G) Representative images and comparisons of CD8+ T cells. Data are pooled from two experiments with n=6 per group (B–G). Values are shown as the mean±SD. *P<0.05; ANOVA with Tukey post hoc test. Scale bar=5 mm (C), 100 µm (E–G). ANOVA, analysis of variance.
Figure 1 Intraperitoneal colon cancer cells established a highly angiogenic and immunosuppressive milieu within the peritoneal cavity. Mice were intraperitoneally implanted with MC38 colon cancer cells and temporal changes were serially analyzed. (A) Schematic diagram depicting the experimental schedule. (B) Representative images and comparisons of peritoneal tumors. (C) Representative images and comparisons of the peritoneal tumor blood vessels. (D) Representative images and comparisons of malignant ascites over time. (E, F) Representative images and comparisons of CD31+ blood vessels (E), and CD11b+ F4/80+ tumor-associated macrophages (TAMs), CD206+ M2-like macrophages, and iNOS+ M1-like macrophages (F). (G) Representative images and comparisons of CD8+ T cells. Data are pooled from two experiments with n=6 per group (B–G). Values are shown as the mean±SD. *P<0.05; ANOVA with Tukey post hoc test. Scale bar=5 mm (C), 100 µm (E–G). ANOVA, analysis of variance.CC BY · PubMed Central
Figure 2 Intraperitoneal colon cancer cells impaired intratumoral lymphocytes by upregulating multiple immune checkpoints. (A) Temporal changes of gene expression levels of splenic and intratumoral CD45+CD3+ lymphocytes in peritoneal tumor-bearing mice. (B) Representative flow cytometric plot and comparison of intratumoral CD8+ T cells expressing PD-1 and/or LAG-3. (C) Representative images and comparisons of tumorous PD-L1+ expression over time. Data are pooled from two experiments with n=3–5 per group (A), n=4–5 per group (B), and n=6 per group (C). Values are shown as the mean±SD. *P<0.05; ANOVA with Tukey post hoc test (A, C), Two-tailed Student’s t-test (B). Scale bar=100 µm (C). ANOVA, analysis of variance; DAPI, 4′6-diamidino-2-phenylindole.
Figure 2 Intraperitoneal colon cancer cells impaired intratumoral lymphocytes by upregulating multiple immune checkpoints. (A) Temporal changes of gene expression levels of splenic and intratumoral CD45+CD3+ lymphocytes in peritoneal tumor-bearing mice. (B) Representative flow cytometric plot and comparison of intratumoral CD8+ T cells expressing PD-1 and/or LAG-3. (C) Representative images and comparisons of tumorous PD-L1+ expression over time. Data are pooled from two experiments with n=3–5 per group (A), n=4–5 per group (B), and n=6 per group (C). Values are shown as the mean±SD. *P<0.05; ANOVA with Tukey post hoc test (A, C), Two-tailed Student’s t-test (B). Scale bar=100 µm (C). ANOVA, analysis of variance; DAPI, 4′6-diamidino-2-phenylindole.CC BY · PubMed Central
Figure 3 STING activation normalized tumor angiogenesis and immunity during peritoneal dissemination of colon cancer. Mice with PCCC were intraperitoneally treated with phosphate-buffered saline (PBS) or STING agonist. (A) Schematic diagram depicting the treatment schedule. (B) Representative images and comparisons of peritoneal tumor nodules, blood vessels, and malignant ascites in the PBS- or STING agonist-treated mice. (C) Representative images and comparisons of CD31+ blood vessels, NG2+ pericyte, CD11c+ dendritic cells, CD8+ T cells, and granzyme B (GzB) within peritoneal tumors. (D) Representative flow cytometric plot and comparison of tumor-infiltrating CD11c+ dendritic cells. (E) Representative flow cytometric plot and comparison of tumor-infiltrating CD4+ or CD8+ T cells. (F) Representative images and comparison of IFN-γ ELISPOT in splenocytes. (G) Representative flow cytometric plot and comparison of effector memory (EM, CD44+CD62L−) and central memory (CM, CD44+CD62L+) T cells within the spleen. Data are pooled from two experiments with n=7 per group (B, C, E, F), n=5 per group (D) and n=4 per group (G). Values are shown as the mean±SD. *P<0.05 vs control; Two-tailed Student’s t-test. Scale bar=10 mm (B, top), 5 mm (B, middle), 2 mm (B, bottom), and 100 µm (C). IFN-γ, interferon-γ; PCCC, peritoneal carcinomatosis of colon cancer; STING, stimulator of interferon genes.
Figure 3 STING activation normalized tumor angiogenesis and immunity during peritoneal dissemination of colon cancer. Mice with PCCC were intraperitoneally treated with phosphate-buffered saline (PBS) or STING agonist. (A) Schematic diagram depicting the treatment schedule. (B) Representative images and comparisons of peritoneal tumor nodules, blood vessels, and malignant ascites in the PBS- or STING agonist-treated mice. (C) Representative images and comparisons of CD31+ blood vessels, NG2+ pericyte, CD11c+ dendritic cells, CD8+ T cells, and granzyme B (GzB) within peritoneal tumors. (D) Representative flow cytometric plot and comparison of tumor-infiltrating CD11c+ dendritic cells. (E) Representative flow cytometric plot and comparison of tumor-infiltrating CD4+ or CD8+ T cells. (F) Representative images and comparison of IFN-γ ELISPOT in splenocytes. (G) Representative flow cytometric plot and comparison of effector memory (EM, CD44+CD62L−) and central memory (CM, CD44+CD62L+) T cells within the spleen. Data are pooled from two experiments with n=7 per group (B, C, E, F), n=5 per group (D) and n=4 per group (G). Values are shown as the mean±SD. *P<0.05 vs control; Two-tailed Student’s t-test. Scale bar=10 mm (B, top), 5 mm (B, middle), 2 mm (B, bottom), and 100 µm (C). IFN-γ, interferon-γ; PCCC, peritoneal carcinomatosis of colon cancer; STING, stimulator of interferon genes.CC BY · PubMed Central
Figure 4 STING activation reprogramed immune phenotype of PCCC. (A) NanoString immune-related gene expression heat map. Red and blue denote upregulated and downregulated genes, respectively. (B) Volcano plot showing the changes of gene expression profiles in STING-activated tumors compared with control tumors. The red line indicates p<0.05. (C) Comparisons of mRNA expression levels for genes related to the Th1 response, Th2 response, IFN-stimulated genes, M1-like, M2-like macrophages, and tumor stroma. (D) Comparisons of transcriptional changes of various immune checkpoints and PD-L1 expression levels in non-immune cells (CD45-), myeloid cells (CD45+CD11b+) and other immune cells (CD45+CD11b−) in tumors. (E) Representative images and comparisons of intratumoral CD11b+ myeloid cells, CD11b+F4/80+ TAMs, CD206+ M2-like TAMs, and iNOS+ M1-like TAMs. (F) Representative flow cytometric plot and comparison of M1-like (F4/80+iNOS+) and M2-like (F4/80+Arginase-1+) TAMs in tumors. (G) Comparisons of expression levels of genes related to macrophage phenotypes in bone marrow-derived macrophages (BMDMs) stimulated with PBS or STING agonist. (H) Comparisons of type-I IFNs expression in BMDMs treated with PBS or STING agonist. Data are pooled from two experiments with n=4 per group (A–C), n=4–6 per group (D), n=7 per group (E), n=5–6 per group (F) and n=6 per group (G, H). Values are shown as the mean±SD. *P<0.05; two-tailed Student’s t-test. Scale bar=100 µm (E). IFN, interferon; IL2, interleukin 2; PCCC, peritoneal carcinomatosis of colon cancer; PBS, phosphate-buffered saline; STING, stimulator of interferon genes.
Figure 4 STING activation reprogramed immune phenotype of PCCC. (A) NanoString immune-related gene expression heat map. Red and blue denote upregulated and downregulated genes, respectively. (B) Volcano plot showing the changes of gene expression profiles in STING-activated tumors compared with control tumors. The red line indicates p<0.05. (C) Comparisons of mRNA expression levels for genes related to the Th1 response, Th2 response, IFN-stimulated genes, M1-like, M2-like macrophages, and tumor stroma. (D) Comparisons of transcriptional changes of various immune checkpoints and PD-L1 expression levels in non-immune cells (CD45-), myeloid cells (CD45+CD11b+) and other immune cells (CD45+CD11b−) in tumors. (E) Representative images and comparisons of intratumoral CD11b+ myeloid cells, CD11b+F4/80+ TAMs, CD206+ M2-like TAMs, and iNOS+ M1-like TAMs. (F) Representative flow cytometric plot and comparison of M1-like (F4/80+iNOS+) and M2-like (F4/80+Arginase-1+) TAMs in tumors. (G) Comparisons of expression levels of genes related to macrophage phenotypes in bone marrow-derived macrophages (BMDMs) stimulated with PBS or STING agonist. (H) Comparisons of type-I IFNs expression in BMDMs treated with PBS or STING agonist. Data are pooled from two experiments with n=4 per group (A–C), n=4–6 per group (D), n=7 per group (E), n=5–6 per group (F) and n=6 per group (G, H). Values are shown as the mean±SD. *P<0.05; two-tailed Student’s t-test. Scale bar=100 µm (E). IFN, interferon; IL2, interleukin 2; PCCC, peritoneal carcinomatosis of colon cancer; PBS, phosphate-buffered saline; STING, stimulator of interferon genes.CC BY · PubMed Central
Figure 5 Type-I IFN signaling and CD8+ T cells are indispensable during STING-induced peritoneal vascular and immune normalization. Mice were injected with MC38 cells intraperitoneally and treated with STING agonist and/or depleting antibodies against IFNAR (αIFNAR), CD4 (αCD4), or CD8 (αCD8). (A) Schematic diagram depicting the treatment schedule for IFNAR depletion study. (B) Representative images and comparison of the peritoneal tumor burden, and comparison of malignant ascites. (C) Representative images and comparisons of CD31+ blood vessels and NG2+ pericyte coverages within tumors. (D) Representative images and comparisons of CD11b+ myeloid cells, CD11b+F4/80+ TAMs, CD206+ M2-like macrophages, and iNOS+ M1-like macrophages within tumors. (E) Representative images and comparison of CD8+ T cells within tumors. (F) Schematic diagram depicting the treatment schedule for CD4 or CD8 depletion study. (G) Representative images and comparison of the peritoneal tumor burden, CD31+ blood vessels and NG2+ pericyte within tumors. Data are pooled from two experiments with n=6 per group (B–E) and n=5 per group (G). Values are shown as the mean±SD p<0.05; ANOVA with Tukey post-hoc test. Scale bar=10 mm (B), 100 µm (C–E), 5 mm (G, top), 100 µm (G, bottom). ANOVA, analysis of variance; IFN, interferon; IFNAR, IFN α receptor; PBS, phosphate-buffered saline; STING, stimulator of interferon genes.
Figure 5 Type-I IFN signaling and CD8+ T cells are indispensable during STING-induced peritoneal vascular and immune normalization. Mice were injected with MC38 cells intraperitoneally and treated with STING agonist and/or depleting antibodies against IFNAR (αIFNAR), CD4 (αCD4), or CD8 (αCD8). (A) Schematic diagram depicting the treatment schedule for IFNAR depletion study. (B) Representative images and comparison of the peritoneal tumor burden, and comparison of malignant ascites. (C) Representative images and comparisons of CD31+ blood vessels and NG2+ pericyte coverages within tumors. (D) Representative images and comparisons of CD11b+ myeloid cells, CD11b+F4/80+ TAMs, CD206+ M2-like macrophages, and iNOS+ M1-like macrophages within tumors. (E) Representative images and comparison of CD8+ T cells within tumors. (F) Schematic diagram depicting the treatment schedule for CD4 or CD8 depletion study. (G) Representative images and comparison of the peritoneal tumor burden, CD31+ blood vessels and NG2+ pericyte within tumors. Data are pooled from two experiments with n=6 per group (B–E) and n=5 per group (G). Values are shown as the mean±SD p<0.05; ANOVA with Tukey post-hoc test. Scale bar=10 mm (B), 100 µm (C–E), 5 mm (G, top), 100 µm (G, bottom). ANOVA, analysis of variance; IFN, interferon; IFNAR, IFN α receptor; PBS, phosphate-buffered saline; STING, stimulator of interferon genes.CC BY · PubMed Central
Figure 6 Combination immunotherapy of the STING agonist and anti-PD-1 antibody further enhanced antitumor immunity in PCCC. (A) Schematic diagram depicting the treatment schedule. (B) Representative images and comparisons of the peritoneal tumor burden. (C) Representative images and comparisons of peritoneal tumor nodules and malignant ascites. (D) Representative images and comparisons of CD31+ blood vessels and NG2+ pericyte coverages within tumors. (E) Representative images and comparisons of CD206+ M2-like macrophages and iNOS+ M1-like macrophages within tumors. (F) Representative images and comparisons of CD8+ T cells and GzB-expressing T cells within tumors. (G) Representative images and comparison of IFN-γ ELISPOT in splenocytes from PBS-treated or STING agonist-treated tumor-bearing mice. (H) Representative images and comparison of caspase 3+ apoptotic cells within tumors. (I) Schematic depicting the mechanism by which intraperitoneal STING activation reprograms the peritoneal vascular-immune microenvironment and enhances the antitumor effect of PD-1 immune checkpoint inhibitor. Data are pooled from two experiments with n=7 per group (B–H). Values are shown as the mean±SD. *P<0.05 vs control; #p<0.05 vs P; $p<0.05 vs S; ANOVA with Tukey post hoc test. Scale bar=10 mm (B), 1 mm (C), 100 µm (D–F, H). GzB, granzyme B; IFN-γ, interferon-γ; PBS, phosphate-buffered saline; PCCC, peritoneal carcinomatosis of colon cancer; STING, stimulator of interferon genes.
Figure 6 Combination immunotherapy of the STING agonist and anti-PD-1 antibody further enhanced antitumor immunity in PCCC. (A) Schematic diagram depicting the treatment schedule. (B) Representative images and comparisons of the peritoneal tumor burden. (C) Representative images and comparisons of peritoneal tumor nodules and malignant ascites. (D) Representative images and comparisons of CD31+ blood vessels and NG2+ pericyte coverages within tumors. (E) Representative images and comparisons of CD206+ M2-like macrophages and iNOS+ M1-like macrophages within tumors. (F) Representative images and comparisons of CD8+ T cells and GzB-expressing T cells within tumors. (G) Representative images and comparison of IFN-γ ELISPOT in splenocytes from PBS-treated or STING agonist-treated tumor-bearing mice. (H) Representative images and comparison of caspase 3+ apoptotic cells within tumors. (I) Schematic depicting the mechanism by which intraperitoneal STING activation reprograms the peritoneal vascular-immune microenvironment and enhances the antitumor effect of PD-1 immune checkpoint inhibitor. Data are pooled from two experiments with n=7 per group (B–H). Values are shown as the mean±SD. *P<0.05 vs control; #p<0.05 vs P; $p<0.05 vs S; ANOVA with Tukey post hoc test. Scale bar=10 mm (B), 1 mm (C), 100 µm (D–F, H). GzB, granzyme B; IFN-γ, interferon-γ; PBS, phosphate-buffered saline; PCCC, peritoneal carcinomatosis of colon cancer; STING, stimulator of interferon genes.CC BY · PubMed Central
Figure 7 Combination of PD-1 blockade and COX2 inhibitor enhanced STING-induced protective antitumor immunity in PCCC. (A) Kaplan-Meier curves for overall survival. Complete regression (CR) is observed in the combination group. (B) Representative images of abdominal cavity, peritoneum, and ascites in CR mice after dual combination therapy. (C, D) Comparisons of mRNA expression levels of Pdl1, Ido1, and COX2 and comparisons of IDO activity in tumor tissues (C) or tumor-draining lymph nodes (D). (E) Schematic diagram depicting the treatment schedule for IDO or COX2 inhibitors. (F) Comparisons of peritoneal tumor burden and malignant ascites. (G) Schematic diagram depicting the treatment schedule for survival analysis and rechallenge. (H) Kaplan-Meier curves for overall survival. #p<0.05, log-rank test. (I) Representative images of abdominal cavity, peritoneum, and ascites in CR mice after triple combination of STING agonist, COX2 inhibitor, and anti-PD-1 antibody. (J) Comparisons of subcutaneous tumor volume in MC38-rechallenged mice. Data are from experiments with n=9 per group (A), n=5 per group (C, D), n=4–5 per group (F), n=8–9 per group (H), n=1–5 per group (J). Values are shown as the mean±SD *P < 0.05 vs control; #p<0.05 vs S+COX2; Two-tailed Student’s t-test (C and D) and ANOVA with Tukey post-hoc test (F and J). Scale bar=10 mm (B and I, left), 5 mm (B and I, middle).
Figure 7 Combination of PD-1 blockade and COX2 inhibitor enhanced STING-induced protective antitumor immunity in PCCC. (A) Kaplan-Meier curves for overall survival. Complete regression (CR) is observed in the combination group. (B) Representative images of abdominal cavity, peritoneum, and ascites in CR mice after dual combination therapy. (C, D) Comparisons of mRNA expression levels of Pdl1, Ido1, and COX2 and comparisons of IDO activity in tumor tissues (C) or tumor-draining lymph nodes (D). (E) Schematic diagram depicting the treatment schedule for IDO or COX2 inhibitors. (F) Comparisons of peritoneal tumor burden and malignant ascites. (G) Schematic diagram depicting the treatment schedule for survival analysis and rechallenge. (H) Kaplan-Meier curves for overall survival. #p<0.05, log-rank test. (I) Representative images of abdominal cavity, peritoneum, and ascites in CR mice after triple combination of STING agonist, COX2 inhibitor, and anti-PD-1 antibody. (J) Comparisons of subcutaneous tumor volume in MC38-rechallenged mice. Data are from experiments with n=9 per group (A), n=5 per group (C, D), n=4–5 per group (F), n=8–9 per group (H), n=1–5 per group (J). Values are shown as the mean±SD *P < 0.05 vs control; #p<0.05 vs S+COX2; Two-tailed Student’s t-test (C and D) and ANOVA with Tukey post-hoc test (F and J). Scale bar=10 mm (B and I, left), 5 mm (B and I, middle).CC BY · PubMed Central

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Metadata

Authors
Lee, S. J., Yang, H., Kim, W. R., Lee, Y. S., Lee, W. S., Kong, S. J., Lee, H. J., Kim, J. H., Cheon, J., Kang, B., Chon, H. J., & Kim, C.
Affiliations
  • CHA University (KR)
  • CHA University Bundang Medical Center (KR)
Corresponding author
  • Chon, Hong Jae
  • Kim, Chan
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2021-06
Volume
9
Issue
6
Pages
e002195
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2020-002195
PMC
PMC8215239
OpenAlex
W3168539558
Cited by
118
References
50
Citations by year
2026: 24 · 2025: 23 · 2024: 24 · 2023: 24 · 2022: 19 · 2021: 4
FWCI
6.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Medical Device Development Fund (202012D21-01)
  • National Research Foundation of Korea (NRF-2020R1A2C2004530, NRF-2020R1C1C1010722)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
Keywords
STING activation, peritoneal carcinomatosis, colon cancer, vascular normalization, tumor microenvironment, M2 macrophages, M1 macrophage polarization, anti-PD-1 therapy, type I interferon, angiogenesis, pericyte coverage, CD8+ T cell infiltration, immune evasion, immunotherapy
MeSH terms
STING Protein, Animals, Colonic Neoplasms, Disease Models, Animal, Humans, Immunotherapy, Membrane Proteins, Peritoneal Neoplasms, Cell Line, Tumor, Mice, Tumor Microenvironment

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