Deep exploration of the immune infiltrate and outcome prediction in testicular cancer by quantitative multiplexed immunohistochemistry and gene expression profiling
Open accessAbstract
Platinum-based chemotherapy is usually curative for patients with testicular germ cell tumors (TGCT), but a subset of patients experience disease progression and poor clinical outcomes. Here, we tested whether immune profiling of TGCT could identify novel prognostic markers and therapeutic targets for this patient cohort. We obtained primary and metastatic TGCT samples from one center. We performed immune profiling using multiplexed fluorescence immunohistochemistry (FIHC) for T-cell subsets and immune checkpoints, and targeted gene expression profiling (Nanostring nCounter Immune panel). Publically available data sets were used to validate primary sample analyses. Nearly all samples had some degree of T-cell infiltration and immune checkpoint expression. Seminomas were associated with increased CD3+ T-cell infiltration, decreased Regulatory T-cells, increased PD-L1, and increased PD-1/PD-L1 spatial interaction compared with non-seminomas using FIHC. Gene expression profiling confirmed these findings and also demonstrated increased expression of T-cell markers (e.g., IFNγ, and LAG3) and cancer/testis antigens (e.g., PRAME) in seminomas, whereas non-seminomas demonstrated high neutrophil and macrophage gene signatures. Irrespective of histology, advanced TGCT stage was associated with decreased T-cell and NK-cell signatures, while Treg, neutrophil, mast cell and macrophage signatures increased with advanced stage. Importantly, cancer/testis antigen, neutrophil, and CD8+/regulatory T-cell signatures correlated with recurrence free survival. Thus, deep immune characterization of TGCT using IHC and gene expression profiling identified activated T-cell infiltration which correlated with seminoma histology and good prognosis. These results may provide a rationale for testing of anti-PD-1/PD-L1 agents and suggest prognostic markers.
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CTLA-4 expression in tumor cells is predominantly found in yolk sack tumors, choriocarcinomas, and teratomas.
“Besides PD-L1 overexpression in GCN, the immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is also highly expressed in TILs regardless of the histological TGCT type, while the expression of CTLA-4 in tumor cells is predominantly found in yolk sack tumors, choriocarcinomas, and teratomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
In seminomas, activated CD3+ T-cell infiltration has favorable prognostic utility.
“Their findings revealed the presence and favorable prognostic utility of activated CD3+ T-cell infiltration, PD-L1 overexpression, and increased spatial interaction between PD-1 and PD-L1 in seminomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
PD-L1 is found in yolk sac tumors, choriocarcinomas, and teratomas.
“found in yolk sack tumors, choriocarcinomas, and teratomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
Non-seminomas exhibit elevated gene signatures associated with neutrophils and macrophages.
“Conversely, non-seminomas exhibited elevated gene signatures associated with neutrophils and macrophages.”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
In seminomas, increased spatial interaction between PD-1 and PD-L1 has favorable prognostic utility.
“Their findings revealed the presence and favorable prognostic utility of activated CD3+ T-cell infiltration, PD-L1 overexpression, and increased spatial interaction between PD-1 and PD-L1 in seminomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
Advanced stages of disease, regardless of histological tumor type, have elevated Treg, neutrophil, mast cell, and macrophage signatures.
“Advanced stages of the disease, regardless of the histological tumor type, were characterized by reduced T-cell and NK-cell signatures, while Treg, neutrophil, mast cell, and macrophage signatures were elevated in these cases [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
In seminomas, PD-L1 overexpression has favorable prognostic utility.
“Their findings revealed the presence and favorable prognostic utility of activated CD3+ T-cell infiltration, PD-L1 overexpression, and increased spatial interaction between PD-1 and PD-L1 in seminomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
CTLA-4 is highly expressed in TILs regardless of histological TGCT type.
“Besides PD-L1 overexpression in GCN, the immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is also highly expressed in TILs regardless of the histological TGCT type, while the expression of CTLA-4 in tumor cells is predominantly found in yolk sack tumors, choriocarcinomas, and teratomas [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
Advanced stages of disease, regardless of histological tumor type, are characterized by reduced T-cell and NK-cell signatures.
“Advanced stages of the disease, regardless of the histological tumor type, were characterized by reduced T-cell and NK-cell signatures, while Treg, neutrophil, mast cell, and macrophage signatures were elevated in these cases [27].”
From The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors (2024) · cites this paper as [27]
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Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Schuster, S. J., Bishop, M. R., Tam, C. S., Waller, E. K., Borchmann, P., McGuirk, J. P., Jäger, U., Jaglowski, S., Andreadis, C., Westin, J. R., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1804980 · Cited by 4,112 · see citing works
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“Siska et al. [27] also investigated the significance of the PD-1/PD-L1 signaling pathway in the immune escape of testicular cancer.”
BackgroundInfluentialAl-Hogbani, M., Duguay, J., Wagner, D.-C., Haferkamp, A., Joubert, P., Frees, S., Rendon, R., Power, N., Périgny, M., & Toren, P. (2021) · Urologic Oncology: Seminars and Original Investigations · doi:10.1016/j.urolonc.2021.02.014 · Cited by 5 · see citing works
- Authors
- Siska, P. J., Johnpulle, R. A. N., Zhou, A., Bordeaux, J., Kim, J. Y., Dabbas, B., Dakappagari, N., Rathmell, J. C., Rathmell, W. K., Morgans, A. K., Balko, J. M., & Johnson, D. B.
- Affiliations
- University Hospital Regensburg (DE)
- Vanderbilt-Ingram Cancer Center (US)
- Vanderbilt University (US)
- Navigate BioPharma (United States) (US)
- Genoptix, Inc., Carlsbad, CA, USA
- Corresponding author
- Siska, Peter J.
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-03-20
- Volume
- 6
- Issue
- 4
- Pages
- e1305535
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5414873
- OpenAlex
- W2600859172
- Cited by
- 82
- References
- 2
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 9 · 2022: 12 · 2021: 12 · 2020: 14 · 2019: 8 · 2018: 9 · 2017: 1
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- National Cancer Institute (K23CA204726, K12CA090625)
- Topics
- Health Sciences › Medicine › Surgery › Testicular diseases and treatments
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- testicular germ cell tumors, seminoma, non-seminoma, tumor immune infiltrate, T cell infiltration, regulatory T cells, PD-1/PD-L1, immune checkpoint, cancer-testis antigens, PRAME, prognostic factors, recurrence-free survival, tumor stage, PD-1/PD-L1 blockade, NanoString gene expression profiling
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