Evaluation of innate and adaptive immunity contributing to the antitumor effects of PD1 blockade in an orthotopic murine model of pancreatic cancer

Abstract

Despite the clinical success of anti-PD1 antibody (α-PD1) therapy, the immune mechanisms contributing to the antineoplastic response remain unclear. Here, we describe novel aspects of the immune response involved in α-PD1-induced antitumor effects using an orthotopic Kras (G12D)/p53(R172H)/Pdx1-Cre (KPC) model of pancreatic ductal adenocarcinoma (PDA). We found that positive therapeutic outcome involved both the innate and adaptive arms of the immune system. Adoptive transfer of total splenocytes after short-term (3 d) but not long-term (28 d) PD1 blockade significantly extended survival of non-treated tumor-bearing recipient mice. This protective effect appeared to be mostly mediated by T cells, as adoptive transfer of purified natural killer (NK) cells and/or granulocyte receptor 1 (Gr1)(+) cells or splenocytes depleted of Gr1(+) cells and NK cells did not exhibit transferrable antitumor activity following short-term PD1 blockade. Nevertheless, splenic and tumor-derived CD11b(+)Gr1(+) cells and NK cells showed significant persistence of α-PD1 bound to these cells in the treated primary recipient mice. We observed that short-term inhibition of PD1 signaling modulated the profiles of multifunctional cytokines in the tumor immune-infiltrate, including downregulation of vascular endothelial growth factor A (VEGF-A). Altogether, the data suggest that systemic blockade of PD1 results in rapid modulation of antitumor immunity that differs in the tumor microenvironment (TME) when compared to the spleen. These results demonstrate a key role for early immune-mediated events in controlling tumor progression in response to α-PD1 treatment and warrant further investigation into the mechanisms governing responses to the therapy at the innate-adaptive immune interface.

Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer

“…Salazar and colleagues demonstrated considerable ICI response in immunocompetent PDAC mice and, thus it is plausible that optimal cytotoxic effects from ICIs in clinical regimens may require both direct PDAC targeting combined with robust immune cell responses. 41…”

Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Restructures the Immune Contexture to Improve Checkpoint Blockade Efficacy

“…Tumor volumes were measured thrice weekly using manual calipers. Lower doses from previously published regimens of anti-PD-1 [ 34 , 42 ] and anti-CTLA-4 [ 43 , 44 ] were chosen to more readily observe potential synergy with shIDO-ST.…”

“…Recently, a novel subset of anti-tumor neutrophils have been identified in the early stages of NSCLC that are capable of inducing anti-tumor immunity through attainment of antigen presentation capabilities [ 30 , 31 , 32 , 33 ]. Our recent studies in pancreatic ductal adenocarcinoma (PDAC) have also shown that depletion of neutrophils and monocytes abrogate the anti-tumor effects of anti-PD-1 treatment, demonstrating the importance of tumor-associated myeloid cells in checkpoint blockade efficacy [ 34 ]. Increasing antigen stimulation of T cells through increased presentation by APCs and/or converted MDSC may sensitize permanently dysfunctional T cells to ICB therapy.…”

Tumor-Associated Macrophages: Protumoral Macrophages in Inflammatory Tumor Microenvironment

“… 71 In pancreatic cancer, infiltrating Treg in tumor microenvironment upregulated CTLA-4 (cytotoxic T-lymphocyte antigen 4) and PD-1, thus, blockage of these pathways enhance anti-tumor immunity. 72 TAMs with CD120a, CD120b secret NO, resulting in promoting the apoptosis of activated T cells in tumor tissue. 73 In pancreatic cancer, CD11b + myeloid cells inhibit CD8 + Tcells by induction of PD-L1 in tumor cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases-dependent manner.…”