Abstract P4-04-11: Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients
Authors: Bernardo Leon Rapoport, Helen C Steel, Carol Ann Benn, Simon Nayler, Teresa Smit, Liezl Heyman, Annette Theron, Nomsa Hlatswayo, Luyanda Kwofie, Pieter Meyer, Ronald Anderson
Journal: Cancer Research (2022)

Abstract Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells can up-regulate or down-regulate these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of positive and negative ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) relative to those of a healthy control group. Method: Soluble ICMs were measured using Multiplex® bead array technology in plasma from 72 BC patients and 45 healthy controls. Data was prospectively obtained and levels compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney &amp; Kruskal-Wallis). Results: Pre-treatment, soluble stimulatory molecules viz. GITR (p&amp;lt;0.0000), GITRL (p&amp;lt; 0.0199), CD27 (p&amp;lt; 0.0243), CD40 (p&amp;lt; 0.0209), ICOS (p&amp;lt; 0.0087), as well as the inhibitory molecules PD-L1 (p&amp;lt; 0.0000), CTLA-4 (p&amp;lt; 0.005), TIM-3 (p&amp;lt; 0.0004), HVEM (p&amp;lt; 0.0004) levels were significantly lower in early BC pts compared to controls. Post treatment, there were significant increases in most ICM levels (Table 1), with the exception of CTLA-4 which decreased significantly following treatment. A pCR was documented in 65% of patients (mostly TNBC). There was no correlation between pre-treatment ICM levels and pCR. Conclusion: We identified low levels of stimulatory and inhibitory ICMs in newly-diagnosed, non-metastatic BC patients compared to healthy controls. Following treatment, with the exception of CTLA-4, most of these pre-treatment abnormalities of systemic ICM levels corrected. NAC is associated with upregulation of sPD-L1 and most other ICMs. These results indicate that early BC is associated with down-regulation of soluble stimulatory and inhibitory ICMs. Newly-diagnosed early BC patients appear to have generalized immune-suppression independent of subtype and stage. To our knowledge, this is the first study to describe the effect of treatment on systemic ICMs in early BC patients. Table 1.The effect of treatment on soluble, systemic ICMsICMControlDiagnosis (Group A)Post-NAC (Group B)Post-surgery (Group C) Group A vs Group BComparing pre-treatment levels vs post-treatment levelsMedian (pg/ml)p-valueBTLA18147130229987127770,0366CD8023291678304836110,0000CD8614297115859922124390,2789CTLA-4261815665986870,0000LAG31504161312754648805001330,0000PD-L133421647479452150,0000PD-1149171230513350150760,8888TIM350473897997596150,0000CD2745773342535154270,0000CD28461353291444277500580,0415CD4019771523203020540,0002GITR37971497403544340,0000GITRL71515886533959270,4938ICOS265061512326586297460,0001HVEM22901865404739500,0000TLR2304772683133837370420,0257 Citation Format: Bernardo Leon Rapoport, Helen C Steel, Carol Ann Benn, Simon Nayler, Teresa Smit, Liezl Heyman, Annette Theron, Nomsa Hlatswayo, Luyanda Kwofie, Pieter Meyer, Ronald Anderson. Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-11.