One line of investigation (Strategic Goals 1,2&4) used a GEMM that targets the expression of the HPV16 oncogenes to basal keratinocytes, eliciting the multistep development of invasive cervical carcinomas in females, as well as dysplasias of the skin in males and females,. The dysplastic and cancerous tissues elicit systemic immuno-suppression (SIS) of the generation and expansion of tumor-antigen-specific T cells, mediated by neutrophils, which is operative in the lymphoid organs as well as in dysplasias and tumors. We have discovered the mechanistic basis, which involves the expression in HPV16-expressing keratinocytes and secretion into the circulation of three members of the IL1 cytokine superfamily, which instructs the bone marrow to produce abundant quantities of demonstrably immunosuppressive neutrophils that then migrate to the spleen and tumor. Translational studies implicate the same mechanism in human cervical cancer. A pan-IL1 inhibitor shuts down the expansion of these immunosuppressive neutrophils, abrogating the SIS, and importantly unlocking an otherwise ineffectual therapeutic vaccine based on the HPV16 E7 oncoprotein. The combination produces significant therapeutic benefit in mouse models, which can be further extended by blocking the CTLA4 immune checkpoint. A manuscript describing the results is being readied for submission to a prominent journal, and the results are being presented at international cancer conferences.
A second line of investigation (Strategic Goals 3&4) involves models of pancreatic neuroendocrine cancer and melanoma and has implicated tumor-associated macrophages (TAMs) in stimulating tumor development and therapeutic resistance mechanisms following standard-of-care therapies. We have found that TAMs are a significant component of both mouse models, being predominantly biased toward a pro-tumoral “M2-like” phenotype. Furthermore, the TAMs exhibit multifaceted capabilities to inhibit the activity of cytotoxic T cells, suggesting that these TAMs play a significant role in evading anti-tumoral immune responses in the tumor microenvironment TME and are therefore a critical component of the intrinsic resistance to immunotherapies. Moreover, we have identified the angiogenic tumor neo-vasculature in pancreatic cancer as a significant barrier to T cell infiltration, one that we are seeking to reprogram it to become a gateway for productive immune attack. These data highlight the instrumental roles of tumor-associated macrophages and tumor vasculature as key components of the immuno-evasive barrier in solid tumors, ones that present new therapeutic vulnerabilities with the potential to elicit more effective anti-tumor immune responses. Translational studies implicate similar mechanisms in the cognate human cancers. A publication in Immunity (PMID: 36630914) describes the reprogramming of the immunosuppressive TME, and in particular of tumor-associated macrophages (TAMs) and endothelial cells, to enable an efficacious T cell attack, using an innovative combination of a synthetic immuno-cytokine (PD1-IL2v) and an immune checkpoint inhibitor (anti-PD-L1). A second manuscript, to be submitted in the coming months, describes the reprogramming of TAMs in melanomas with three distinctive mechanism-targeted drugs that convert TAMs from being tumor-promoting to instead enhancing the efficacy of standard of care therapies. The results will also be presented in international cancer conferences.
