Date of Award
Doctor of Philosophy (PhD)
Robert H. Vonderheide
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a 9% survival rate and rising incidence. Currently, surgical resection remains the only means of curing PDA. Unfortunately, most PDA continues to be diagnosed at advanced or metastatic stage and are unresectable. As such, there is great need to extend immunotherapy to the treatment of PDA. However, PDA has proven to be almost universally unresponsive to immune checkpoint blockade (ICB), consistent with impaired or absent anti-tumor T cell immunity in this disease.
Here, we present evidence that type 1 conventional dendritic cells (cDC1s) – the critical antigen presenting cells (APCs) for anti-tumor T cell priming – are dysregulated early in preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasG12D Trp53R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal upregulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation. This drives increased CD8+ and CD4+ T cell activation, resulting in improved response to vaccination and superior control of tumor outgrowth.
We also present evidence of a central role for CD4+ T cells in the response to CD40 agonist. Our group has previously shown that systemic activation of CD40 drives T cell infiltration into KPC tumors. Combination treatment with CD40 agonist and immune checkpoint blockade (ICB) leads to durable tumor regressions that are both CD8+ and CD4+ T cell-dependent. Yet, the mechanisms by which CD4+ T cells infiltrate tumors following CD40 agonist remain unknown. Here, we use single-cell transcriptomics to query immune populations within the tumor microenvironment after various combinations of CD40 agonist and ICB. We discover that intratumoral myeloid cells produce the chemokine CCL5 following CD40 activation, mediating CD4+ T cell influx into the tumor microenvironment. Disruption of CCL5 genetically or pharmacologically mitigates the influx of CD4+ but not CD8+ T cells into tumors and diminishes therapeutic efficacy, resulting in impaired immune control of tumor outgrowth.
Thus, our studies reveal the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggest therapeutically tractable strategies towards cDC1 repair while highlighting a previously unappreciated role for CCL5 in CD4+ T cell intratumoral chemotaxis in response to immunotherapy.
Lin, Jeffrey Howard, "Type 1 Conventional Dendritic Cells Are Systemically Dysregulated Early In Pancreatic Carcinogenesis" (2020). Publicly Accessible Penn Dissertations. 4107.