α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas

EMT enables carcinoma cells to exert local immunosuppression by repressing MHCI antigen presentation and antigen processing/presentation machinery, thereby suppressing CD8+ T cell and NK cytotoxic activities.

“Of further therapeutic relevance, EMT enables carcinoma cells to exert local immunosuppression143,144. EMT confers repression of major histocompatibility complex class I (MHCI) antigen presentation by tumor cells, which is required for recognition by CD8+ T cells, and thus indirectly suppresses cytotoxic activities of CD8+ T cells and cytolytic activities of NK cells141,143–145.”

Treg cells functionally repress the tumor-killing activity of CD8+ T cells through various activities, including TGF-β1 activation.

“These then functionally repress, through various activities, including TGF-β1 activation82,145, the tumor-killing activity of CD8+ T cells 58,63,82,145,218,219”

Treg cells contribute to macrophage and neutrophil polarization towards a regenerative rather than inflammatory cell state.

“and contribute to macrophage and neutrophil polarization towards a regenerative rather than inflammatory cell state58,63,82,145,172,173,218,219.”

Recent results highlight the role of increased TGF-β signaling in intrinsic resistance to checkpoint blockade therapy.

“Recent results in fact highlight the role of increased TGF-β signaling in intrinsic resistance to checkpoint blockade therapy21,23,38,71,145.”

Monoclonal antibodies prevent TGF-β receptors from binding ligand.

“Another class of therapeutics comprises monoclonal antibodies that prevent TGF-β receptors from binding ligand145,300.”

TGF-β released and activated by cancer cells, stromal fibroblasts, and/or immune cells dampens anti-tumor immunity and responses to immunotherapeutics through direct and indirect mechanisms.

“An underlying and predominant rationale focuses on the ability of TGF-β released and activated by cancer cells, stromal fibroblasts and/or immune cells to dampen anti-tumor immunity and responses to immunotherapeutics through direct and indirect mechanisms21,23,71,145,353,354.”

Anti-PD-1 therapy by itself promotes intratumoral TGF-β signaling in mouse models.

“Moreover, anti-PD-1 therapy by itself promotes intratumoral TGF-β signaling in mouse models145.”

The anti-PD-L1-TβRII chimera M7824 demonstrated increased efficacy of tumor regression in some mouse models compared with TβRII trap alone or anti-PD-L1 monotherapy.

“The anti-PD-L1-TβRII chimera, M7824, also demonstrated increased efficacy of tumor regression in some mouse models, when compared to TβRII trap alone or anti-PD-L1 monotherapy366, consistent with results from combinations of anti-TGF-β or anti-PD-1/PD-L1145.”

TGF-β, CTLA-4, and PD-L1/PD-1 signaling act as parallel immunosuppressive pathways that repress cytotoxic T cell, NK cell, and macrophage activities through distinct mechanisms.

“Considering that TGF-β, CTLA-4 and PD-L1/PD-1 signaling act as parallel immunosuppressive pathways that repress cytotoxic T cell, NK cell and macrophage activities through distinct mechanisms”

Treatments combining TGF-β inhibition with immune checkpoint inhibition are likely to increase therapeutic efficacy.

“treatments that combine TGF-β inhibition with immune checkpoint inhibition are likely to increase therapeutic efficacy21,23,71,145,346,362.”

In a preclinical study of six SCC lines, CD4+ T cell composition distinguished responsive lines from those refractory to anti-TGF-β/anti-PD-1 combination therapy in vivo.

“In a preclinical study of six SCC lines, the CD4+ T cell composition distinguished responsive lines from those refractile to anti-TGF-β/anti-PD-1 combination therapy in vivo145.”