Abstract IA01: Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy

Abstract

Abstract Complex interactions between the immune system and cancer influencing tumor invasion, metastasis, and treatment outcomes are poorly understood. Similar to the influence of intra- and inter-tumoral genetic heterogeneity on response and resistance to molecularly targeted therapies, immunologic heterogeneity may explain the outgrowth of resistant tumor clones under the selection pressure of immunotherapy. Evidence for this phenomenon emerged from the results of high-dose IL-2 therapy, with responding metastases showing brisk CD8+ T cell infiltration, while non-responding lesions in the same patients were lymphocyte-poor. It has also been shown in patients receiving adoptive cell transfer therapies (TILs, CARs), with initial tumor regression followed by the outgrowth of tumors that have down-regulated target antigens. More recently, clinical experience with drugs blocking immune checkpoint molecules such as CTLA-4, PD-1 and PD-L1 has revealed unconventional response patterns in 5-10% of patients, including mixed tumor regressions (simultaneous progression/regression at different metastatic sites in an individual patient). Our investigations of the immunosuppressive ligand PD-L1, expressed by many human tumors, as a potential biomarker of response to anti-PD-1 therapy have revealed intra-tumoral as well as inter-tumoral heterogeneity of expression. Within individual tumor lesions, PD-L1 protein expression (IHC) can be patchy or focal, co-localizing with lymphoid infiltrates. Further study on a molecular level revealed expression of IFN-g in the same microenvironment as PD-L1, along with PD-1 and other immunosuppressive molecules, generating the adaptive immune resistance hypothesis. Examination of PD-L1 protein expression in multiple tumor lesions from individual patients showed variability over time and at distinct anatomic sites, consistent with the dynamic and context-dependent nature of immune responses, suggesting that inter-lesional variability could influence susceptibility to anti-PD-1 or PD-L1 therapy. Innovative approaches such as neoadjuvant immunotherapy trials or rapid autopsy analysis are needed to gain a deeper knowledge of tumor immunologic heterogeneity and potential intersections with genetic heterogeneity. This will be critical to understanding the evolution of anti-tumor immunity and developing more effective immune-based and combinatorial therapies. This work was supported by grants from Bristol-Myers Squibb, the National Cancer Institute (R01 CA142779), the Melanoma Research Alliance, the Barney Family Foundation, the Dermatology Foundation, and Stand Up To Cancer. Citation Format: Suzanne L. Topalian. Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA01.