Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape

Abstract

Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti–programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor–β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti–PD-1 antibody in mice harboring syngeneic tumors refractory to anti–PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti–PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.

Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors

“…Studies found that TGF-β was associated with poor clinical outcomes and limited the response of anti-PDL1 therapy which was attributed to T cell exclusion in urothelial and colorectal cancer ( Mariathasan et al, 2018 ; Tauriello et al, 2018 ). TGF-β1, the universal isoform of TGF-β, presents in many human cancers and contributes to anti-PD1 resistance ( Martin et al, 2020 ). Tumor-derived chemokines recruit immunosuppressive cells including Tregs, macrophages and MDSCs to the TME to create an immunosuppressive but tumor-supportive environment, interfering the immunotherapy targeting adaptive immune resistance ( Roussos et al, 2011 ).…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…As a direct TGF-β-targeting agent, the high-affinity artificial TGF-β1 antibody SRK-181 has been employed successfully in anti-PD-1 cancer treatments to override immunotherapy resistance. Equally, the co-administration of SRK-181 and anti-PD-1 has also demonstrated increased anti-tumour effects and survival benefits in bladder cancer-bearing mice by increasing infiltering CD8+ T cells and decreasing immunosuppressive myeloid cells [ 145 ]. Another chemical TGF-β inhibitor, tranilast, which was originally developed as an antiallergic drug, has also demonstrated proven anti-fibrosis and anti-tumour effects.…”

Decoding cancer’s camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

“…TGF-β is expressed in cancer, stromal and immune cells in three isoforms, TGF-β1, β2, and β3. Several pan-cancer gene expression analyses have shown that TGF-β1 is the primary isoform expressed in tumors, while TGF-β3 is less frequently observed and TGF-β2 is rarely detected and mainly serves to regulate normal cardiac function and hematopoiesis, which helps explain the failure of earlier pan-TGF-β targeting therapies due to toxicity-related adverse events [108,147,148] . The most common proposed mechanisms of TGF-β-driven ICB resistance are CD8+ T cell exclusion via fibroblast differentiation and subsequent stromal remodeling and inhibition of CD4+ T helper cell differentiation to the immune-activating T-helper (Th)1 effector cell phenotype, as these conditions have been reproduced in various mouse tumor models and effectively treated by combined targeting of TGF-β and the PD-1/PD-L1 axis [149][150][151][152] .…”