Challenges and Opportunities for Pancreatic Cancer Immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDA) is among the most immune-resistant tumor types. Its unique genomic landscape shaped by oncogenic drivers promotes immune suppression from the earliest stages of tumor inception to subvert adaptive T cell immunity. Single-agent immune modulators have thus far proven clinically ineffective, and multi-modal therapies targeting mechanisms of immunotherapy resistance are likely needed. Here, we review novel immunotherapy strategies currently under investigation to (1) confer antigen specificity, (2) enhance T cell effector function, and (3) neutralize immunosuppressive elements within the tumor microenvironment that may be rationally combined to untangle the web of immune resistance in PDA and other tumors.

Keywords: immunotherapy; pancreatic cancer.

Figure 1:. Overcoming mechanisms of PDA immune resistance.

PDA immunotherapy resistance is driven by its unique genetic landscape. Downstream signaling of mKRAS directly averts innate and adaptive anti-tumor immunity by enhancing autophagocytosis to decrease tumor MHC-I expression and increase expression of PD-L1 and CD47. mKRAS signaling promotes tumor-intrinsic GM-CSF and CXCL1 expression leading to MDSC infiltration and T-cell exclusion. Additionally, downregulation of CCL4 via mKRAS-mediated WNT/β-catenin activation impedes DC recruitment and IL-6 expression leads to systemic cDC1 paucity. mKRAS also promotes factors leading to chronic inflammation and expansion of the fibroinflammatory stroma such as Sonic Hedgehog signaling, COX2, pSTAT3, IL-6 and matrix metalloproteinase 7 (MMP7). Deficiency of p53 also promotes TAM polarization to immunosuppressive M2 phenotype. Rational combination of multi-modal immune modulatory strategies that (1) confer antigen specificity (yellow), (2) enhance innate (red) and adaptive (blue) immune cell effector function and (3) neutralize immunosuppressive elements within the tumor microenvironment (purple) are likely required to overcome PDA immune resistance. APC – antigen presenting cell, ATCT – adoptive T-cell therapy, FAKi – focal adhesion kinase, HCQ – hydroxychloroquine, FAP – fibroblast activation protein, MDSC – myeloid-derived suppressor cell, mKRAS – mutant KRAS, RT – radiation therapy, SHH – Sonic Hedgehog, TAM – tumor-associated macrophage, Vax – cancer vaccine, VitD – vitamin D.