Abstract B23: Combination of SOS1::KRAS inhibitor with a MEK inhibitor reconfigures the immune tumor microenvironment of KRASG12D pancreatic ductal adenocarcinomas and sensitizes to immunotherapy

• Published in: Cancer immunology research 2022-12, Vol.10 (12_Supplement), p.B23-B23
• Main Authors: Norgard, Robert J, Budhani, Pratha, O'Brian, Sarah, Potts, Jessica, Flynn, Brianna, Salce, Xavier, Tagore, Joshua, Thiede, Lucinda, Seco, Joseph, Segal, Suzanne, Love, Mark, Mikucka, Ania, Cote, Charlie, Wasti, Ruby, Kamalakannan, Mohanapriya, Jeschko, Astrid, Melo-Zainzinger, Gabriela, Mcnabola, Angela, DiBlasi, Varenka Rodriguez Rodriguez, Tumang, Joseph, Tontsch-Grunt, Ulrike, Hinkel, Melanie, Pignatelli, Jeanine, Trapani, Francesca, Martinez-Morilla, Sandra, Kostyrko, Kaja, Hofmann, Marco H, Kashyap, Abhishek, Flano, Emilio, Liu, Kang
• Format: Article
• Language: English
• ISSN: 2326-6074; 2326-6074
• DOI: 10.1158/2326-6074.TUMIMM22-B23

KRAS is most frequently mutated in pancreatic adenocarcinomas (PDAC) with more than 90% of cases having a KRAS mutation. This leads to constitutive activation of the downstream signaling pathways, driving tumor cell proliferation whilst co-opting the tumor microenvironment (TME) to promote tumorigenesis and immune escape. The mutant specific KRASG12C inhibitor (AMG510) has been shown to suppress tumor growth and reconfigure the immune TME. However, covalent binding KRASG12C inhibitors have no efficacy on other KRAS alleles, such as G12D and V, the majority of KRAS mutations in PDAC (37% and 28%, respectively). Here, we use a SOS1 inhibitor (BI 1701963) in combination with a MEK inhibitor, blocking two non-redundant steps in the KRAS pathway, on a library of congenic tumor clones derived from an autochthonous mouse model of PDAC deemed the KPCY (Pdx-1-Cre, KRASG12D, p53-/-, YFP+). These tumor lines can generate both “hot” and “cold” TMEs regarding T cell infiltration. We observed that combined SOS1 and MEK inhibition suppressed tumor growth of all KPCY lines irrespective of their cold or hot TME status. In some KPCY lines, CD8 T-cells significantly increased in the TME following combination treatment. We found that the CD8 T-cell increase is restricted to the individual tumor site and resulted from both recruitment and intra-tumoral division. This was accompanied by a decrease of tumor associated macrophages and myeloid-derived suppressor cells. Single-cell RNAseq profiling of the TME was performed on three KPCY lines with distinct immune response to the treatment to characterize cellular composition change induced by the SOS1 and MEK inhibitor combination. To take advantage of the treatment-induced immune TME reconfiguration, we examined combination immune-oncology (IO) targeting T cells and antigen-presenting cells and found that the combination of SOS1i and MEKi with PD-1/CTLA4/CD40 enhanced and prolonged tumor growth inhibition mediated by anti-tumor immunity. Collectively, these results reveal that the combination of SOS1 and MEK inhibitors can be used to convert cold to hot tumors and highlights how we can rationalize combination of cancer-targeted therapy and IO therapy to prolong anti-tumor effects. Citation Format: Robert J Norgard, Pratha Budhani, Sarah O'Brian, Jessica Potts, Brianna Flynn, Xavier Salce, Joshua Tagore, Lucinda Thiede, Joseph Seco, Suzanne Segal, Mark Love, Ania Mikucka, Charlie Cote, Ruby Wasti, Mohanapriya Kamalakannan, Astrid J