Abstract 2372: Tumoral p53 mutations differentially mediate poor T-cell infiltration and autologous T-cell killing in preclinical models

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 13_Supplement; p. 2372
• Main Authors: Silverman, Deborah A., Ashkin, Emily, Whitfield, Benjamin, Punt, Simone, Manrique, Soraya Zorro, Wang, Yunfei, Korkut, Anil, Williams, Leila, Zhang, Minying, Kotler, Eran, Oren, Moshe, Maitra, Anirban, Hwu, Patrick
• Format: Journal Article
• Language: English
• Published: 01-07-2019
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-2372

Abstract
Harnessing the immune system through the attenuation of endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection in multiple solid tumors; however, most cancer types remain resistant to immunotherapy. It is imperative to understand the unique mechanisms by which these lethal malignancies evade the immune system in order to design efficacious therapies. Research by several groups is elucidating how overall mutational burden, tumor stroma, and patient microbiome predict response to immunotherapies in immune-resistant cancers. However, the frequency and distribution of driver mutations in the tumors themselves differ between immunogenic and non-immunogenic cancer types and may play a role in immune escape. Whereas p53, the most commonly mutated gene in cancer, is mutated in 70-90% of non-immunogenic tumors like pancreatic adenocarcinoma (PDAC), it is mutated in only 10-15% of immunogenic skin cutaneous melanoma cases. Loss of p53 through truncating mutations mediates tumor escape from apoptosis and senescence. Furthermore, many p53 missense mutations (mtp53) not only lose wild-type activity (LOF), but acquire novel gain-of-function (GOF) activities which promote oncogenesis and resistance to therapy. Pre-clinical data suggest that mtp53 differentially mediates tumor escape from immune surveillance by altering the innate immune response, including NK cell function and macrophage phenotype, thereby allowing tumorigenesis through chronic local immunosuppression. Few studies have been completed, however, to demonstrate the role of mtp53 in regulating the adaptive immune response. Understanding the role of p53 and its mutants in the regulation of T-cell function in cancer would provide a novel framework by which to understand and overcome resistance to cancer immunotherapy in many deadly cancer types. We hypothesize that mtp53 mediates evasion of T-cell anti-tumor activity, and that gain-of-function pathways downstream of mtp53 drive this process. Here we elaborate on previously presented work, elucidating how GOF vs. LOF mtp53 influences T-cell infiltration and killing using both novel model systems. Ultimately, these results may define a new role for mtp53 in influencing the immune system, and provide a rationale for developing effective combination strategies to improve response to immunotherapy.
Citation Format: Deborah A. Silverman, Emily Ashkin, Benjamin Whitfield, Simone Punt, Soraya Zorro Manrique, Yunfei Wang, Anil Korkut, Leila Williams, Minying Zhang, Eran Kotler, Moshe Oren, Anirban Maitra, Patrick Hwu. Tumoral p53 mutations differentially mediate poor T-cell infiltration and autologous T-cell killing in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2372.