Neoantigens Elicit Protumorigenic Immune Responses in Pancreatic Cancer

Immunotherapies have generally not been effective treatments for pancreatic ductal adenocarcinoma (PDAC), a fact that has typically been attributed to a dearth of tumor-infiltrating CD8⁺ T cells and an immunosuppressive tumor microenvironment (TME). However, some recent studies have suggested that some human PDACs do have intratumoral T cells and express neoantigens, prompting Hegde and colleagues to examine why T cell–mediated immunity is limited in this disease. Experiments employing a mouse model of PDAC expressing a model neoantigen revealed that, in the initial stages of tumorigenesis, neoantigen expression elicited antigen-specific T-cell responses, indicating that the early PDAC TME is not markedly immunosuppressive. Counterintuitively, neoantigen expression accelerated PDAC progression and reduced survival, whereas expression of the same neoantigen in a mouse model of lung adenocarcinoma had the opposite effect. Further, neoantigen-expressing PDACs did not respond well to anti–PD-1 or anti-CTLA4. Deeper investigation revealed that, unlike in lung adenocarcinomas, neoantigen expression in PDACs elicited a protumorigenic T_h17 response. Analyses of mouse and human tumors showed that conventional dendritic cells (cDC) were fewer in number and less functional in PDACs compared with lung adenocarcinomas, which may mean that suboptimal cDC-mediated T-cell priming against neoantigens in PDAC compared with lung adenocarcinoma underlies the previously observed differences. Providing more evidence for this hypothesis, hematopoietic stimulation of cDC mobilization into early-stage pancreatic lesions triggered a transition from the tumorigenic T_h17 response to neoantigens to an antitumor response mediated by T_h1 and CD8⁺ T cells. Additionally, cDC mobilization into established PDACs caused disease stabilization, and stimulation of cDC mobilization combined with anti-CD40 agonist treatment (to enhance licensing as well as function and survival of antigen-presenting cells) and radiotherapy caused tumor regression, even in mice not expressing the model neoantigen. Together, these results elucidate a previously unknown mechanism explaining T-cell ineffectiveness in PDAC and provide hints about potentially effective therapeutic combinations in this immunotherapy-recalcitrant malignancy.

Hegde S, Krisnawan VE, Herzog BH, Zuo C, Breden MA, Knolhoff BL, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 2020;37:289–307.E9.

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