Background: Neoadjuvant chemotherapy followed by radical cystectomy is the optimal treatment for patients with muscle invasive bladder cancer. Between 30 and 40% of patients receiving neoadjuvant chemotherapy will have pathological complete response at the time of radical cystectomy. Presence of somatic mutations in DNA damage repair genes correlate with chemoresponse, likely stemming from a loss-of-function in the ability to repair DNA damage brought on by cytotoxic chemotherapy. However, many chemoresponders have WT DNA repair status. As such, there is a keen interest to identify additional mechanisms associated with chemoresponse.
Results: A higher tumor mutation/neoantigen burden is associated with response to immune checkpoint blockade, so we sought to investigate a correlation between mutation burden and chemoresponse. We found that responders had a higher neoantigen burden and higher signature of tumor infiltrating CD8+ T cells (TILs). We interrogated a database of tumors that underwent clinical tumor sequencing (NextGen SEQ, Caris Life Sciences; 592 genes; n=897) and PD-L1 staining (Combined Positive Score [CPS] using 22C3 antibody) and found that mutation burden was directly proportional to CPS. In addition, we found that CPS was positively associated with KRAS and TP53 mutation, whereas it was negatively associated with FGFR3 activating alterations, MDM2 amplification and GATA3 amplification after correction for multiple comparisons. There was an overall increase in the proportional representation of TIL-derived T cell receptors (TCR) repertoire in the periphery after chemotherapy independent of responder status. This implies that the presence of immune response even in patients without pathologic response. Additionally, TIL-derived TCRs were also found in perivesical lymph nodes in both responders and non-responders, however, there was a distinct profile of activation/exhaustion associated with either patient group. Responders showed a unique CD69+/PD1−(activated/non-exhausted) population amongst the nodal CD8+ T cells suggesting that this population is required to achieve pathologic complete response.
Conclusions: These results further our understanding of immune responses to chemotherapy in bladder cancer and may enable the development of chemo-immunotherapy regimens to improve response rates to neoadjuvant chemotherapy.
Citation Format: Rashida Ginwala, Alexander Macfarlane, IV, David Liu, R K. Alpaugh, Joanne Xiu, Zoran Gatalica, W M. Korn, Eliezer M. Van Allen, Kerry S. Campbell, Alexander Kutikov, Elizabeth Plimack, Philip H. Abbosh. Immune correlates of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6624.