Thursday, May 15, 2025
5/15/2025
Discovery of host genetic elements affecting response to immune checkpoint inhibitors - PROJECT SUMMARY Abrogating immune checkpoint control has proven to be a powerful therapeutic strategy against cancer with documented long-term remissions in refractory metastatic disease. However, only a subset of patients (10-40%) have meaningful responses. While intrinsic tumor factors play a role in predicting immune checkpoint inhibitor (ICI) outcomes, germline variations in host immune genes are also likely to have a significant impact given their importance in defining immune response and autoimmunity. That both the tumor and the host genomes vary makes the identification of germline factors modifying ICI response highly challenging. We have solved this problem by devising a mouse experimental platform that “fixes” the genomic configuration of the tumor as a transplantable cell line (MC38) while varying germline host genetics, thus permitting the unbiased mapping of quantitative trait loci (QTL) for anti-tumor response after anti-PD1 (aPD1) therapeutics. By crossing Collaborative Cross (CC) multiparent recombinant inbred lines with the C57BL/6 strain, the resultant F1s have genetic variability but will accept the MC38 transplant. In preliminary data, we show that host genetics accounts for 42% of the variation in aPD1 response (heritability, H2) and have mapped aPD1 response to four QTLs on mouse (m)Chr 5, 9, 15, and 17 enriched for immune genes. By selective intercrosses between responder and non- responder CC lines, we found significant epistatic interactions between chromosomes 5 and 17 and between 15 and 17. We devised a cross-species tumor microenvironment (CST) algorithm that reduced the ~1,500 genes in the QTLs to 48 top candidate genes that could predict ICI response in human trials, outperforming current theranostic biomarkers. Based on these data, we propose to expand and refine the QTL map for ICI response in the MC38 model with a focus on defining the genetic mechanisms for the epistatic interactions (Aim 1). In Aim 2, we will challenge the three top candidate genes, Csf2rb and Il2rb (mChr15) and Il10ra (mChr9), with available recombinant cytokines and blocking antibodies towards predicted changes in aPD1 response. These perturbations will allow us to further map the genetic network that establishes the optimal tumor immune microenvironment. We will then expand our studies by mapping the QTLs associated in the murine mammary cancer model AT3 (Aim 3). We anticipate that new QTLs for response will be uncovered. Finally, in Aim 4, we will use the CCF1 tumors to optimize an innovative in vitro micro-organosphere (MOS) platform that encapsulates cells of the tumor microenvironment in a permeable microcapsule amenable to pharmacological intervention and cellular interrogation. Once optimized, we will test a panel of ICI drugs alone and in combination on both murine and human tumors. The success of the proposed work will not only identify potential new biomarkers and new targets for augmenting clinical ICI response, but also will establish a validated platform for the discovery of host genes involved in the response to any immune checkpoint inhibitor.
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