(UroToday.com) In a Keynote Lecture, Dr. Amir Horowitz detailed work done at Mt. Sinai in conjunction with urologic oncologist Dr. John Sfakianos on understanding the importance of HLA-E and NKG2A in BCG treated tumor samples.
Dr. Horowitz first reviewed that NK cell activation is dependent on the collective strength of inhibitory and activating signals, including NKG2D, CD40L, IL-15Rα, GITR, among others. Then, the discussion was focused on the interaction between NKG2A expressed by NK and T cells and HLA-E by the accessory cell. This ligand/receptor interaction, much like the PD-1/PD-L1 axis, can serve as an inhibitory checkpoint for CD8+ T cells. The previous experiments1 have demonstrated that following CRISPR knockout of HLA-E, experimental melanoma models became very sensitive to combination treatment using anti-PD-1 inhibitor and GVAX. Additionally, an anti-NKG2A mAb has been demonstrated to unleash both T and NK cell cytolytic activity2, firmly establishing NKG2A as an alternative axis of immune inhibition. Dr. Horowitz and Sfankiano’s recent work3 has demonstrated that NKG2A is increasingly expressed by tumor-infiltrating CD8 T cells following PD-1 and other immune checkpoint treatments. Furthermore, these NKG2A+ CD8 T cells were shown to react against HLA-ABC deficient tumor cells through TCR-independent innate-like immune reactivity. With the blockade of NKG2A, this innate immune activity was further enhanced.
In BCG-treated tumors, the group found that there is an invariable induction of the TH1 response underpinned by strong IFN-γ induction. Through spatial IHC analyses, the group was further able to delineate adaptive immune resistance, whereby tumor cells not only increase their PD-L1 expression, but also their HLA-E expression. In addition, abundant infiltrating lymphocytes were found surrounding many tumor nests, with an apparent lack of cytotoxicity. These lymphocytes were apparently guided towards to the TME by high expression levels of chemokines CXCL9/10/11. To unravel this conundrum, the group used spatial sequencing that allows for co-localization of gene expression within the 2D tissue architecture. Through this analysis the group elegantly demonstrated preferential tumor infiltration of NK and T cells in tumor nests with high HLA-E expression. As well, in samples collected following BCG treatment, the distance between tumor nests and NK/CD-8+ T cells seemed to be reduced. Neighbors analysis further showed universal increased expression of IFN-γ pathway factors as well as other immune checkpoints on tumor cells with a large number of neighboring immune cells.
From their work, Dr. Horowitz hypothesized that BCG-unresponsive tumors will be sensitive to combination NKG2A/PD-L1 blockade. Moreover, the group’s collective work points to the importance of understanding the timing of tumor recurrence in the context of BCG-mediated immune activation and exhaustion. The tandem investigators are in the process of proposing a phase II trial using combination checkpoint blockade in BCG-unresponsive NMIBC using durvalumab and monalizumab, in which a slew of correlative science work will be performed on tissue, urine and blood samples collected prior to, during and after treatment.
Presented by: Amir Horowitz, Ph.D., is an Assistant Professor of Oncological Sciences and a member of the Precision Immunology Institute and the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, NY
Written by: Roger Li, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain
References:
- Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
- André P, Denis C, Soulas C, et al. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018;175(7):1731-1743.e1713.
- Salomé B, Sfakianos JP, Ranti D, et al. NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer. Cancer cell. 2022;40(9):1027-1043.e1029.