Abstract
Background: Although platinum-based chemotherapy is standard treatment for pancreatic ductal adenocarcinoma (PDAC) patients with germline/somatic mutations in homologous recombination (mutHRD), a subset become platinum-resistant. We have shown that patients with mutHRD PDAC progressing on platinum chemotherapy respond to dual immune checkpoint blockade (ICB) with anti-PD1+CTLA-4. We sought to model these clinical findings in preclinical models to interrogate mechanisms in platinum-resistant mutHRD PDAC that drive ICB sensitivity. Methods: We examined the association between objective disease response following anti-PD1+CTLA-4 ICB and duration of platinum chemotherapy exposure in platinum-resistant mutHRD PDAC patients. Cisplatin- resistant and sensitive Brca2-silenced (via shRNA knockdown) KPC cancer cells were generated and characterized in vitro and in vivo. Results: In 12 mutHRD PDAC patients treated with salvage dual ICB after progression on platinum-based chemotherapy, 7 (58%) demonstrated either partial response or stable disease. Notably, duration of prior platinum exposure was associated with post-ICB disease response. To model these findings preclinically, syngeneic mice implanted with cisplatin-sensitive or resistant shBrca2 or wildtype KPC tumor cells and subsequently treated with gemcitabine+cisplatin chemotherapy demonstrated expected rapid tumor growth of cisplatin-resistant shBrca2 tumors. However, we observed a profound reduction in tumor volumes when these chronically cisplatin-resistant KPC-shBrca2 tumors were subsequently treated with anti-PD-1+CTLA4 ICB, compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumors (P<0.001). To understand mechanistic underpinnings of these observations, whole transcriptome sequencing revealed significant differential upregulation of type1 interferon and cGAS-STING pathways in cisplatin-resistant KPC-shBrca2 tumor cells compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 controls (P-adj≤0.05). Confocal immunofluorescence imaging confirmed constitutively upregulated cGAS and STING expression in cisplatin-resistant KPC-shBrca2 compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumor cells. Activation of type1 interferon/STING manifested in a secretome enriched for T-cell trafficking cytokines CXCL10, CXCL9, and CCL5 from cisplatin-resistant KPC-shBrca2 cells. Intriguingly, evaluable mutHRD patient tumors responsive to dual ICB also demonstrated baseline increase in CXCL9/10 and CCL5 expression compared with ICB-resistant mutHRD tumors (n=3 each) via Nanostring analysis. As such, we observed increased transwell (in vitro) and intratumoral (in vivo) CD8+ T-cell trafficking to cisplatin-resistant KPC-shBrca2 tumors compared with cisplatin-sensitive KPC-shBrca2 controls. Conclusions: Chronicity of platinum exposure in mutHRD PDAC potentiates ICB sensitivity via induction of cell-autonomous type-1 interferon/cGAS-STING signaling and ensuing T-cell trafficking to the PDAC tumor microenvironment.
Citation Format: Ifeanyichukwu Ogobuiro, Anna Bianchi, Lucas Caeiro, Haleh Amirian, Luis Nivelo, Iago De Castro Silva, Karthik Rajkumar, Andrew Adams, Vanessa Garrido, Samara Singh, Nagaraj Nagathihalli, Nipun Merchant, Ramiro Verdun, Peter Hosein, Jashodeep Datta. Chronic platinum exposure induces cell-intrinsic type1 interferon/STING pathway activation in homologous recombination-deficient pancreatic cancer to drive sensitivity to checkpoint immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C064.