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SDIRSACR Oncology Insights

Nivo monotherapy. Pathologic response in the Nivo+Rela arm correlated with increased CD8⁺ T cell infiltration post-
treatment. Nivo+Rela treatment expanded and reprogrammed exhausted CD8⁺ TIL characterized by type I interferon
and exhaustion gene signatures into effector and tissue-resident memory (TEM/TRM) phenotypes. In contrast,
Nivo+Ipi expanded pre-existing TEM/TRM CD8⁺ TIL without rejuvenating exhausted cells. CD8⁺ TCR diversity increased
in major responders to Nivo+Rela but not to Nivo+Ipi, and both combination regimens demonstrated minimal clonal
replacement, suggesting a reliance on baseline TIL pools.
Conclusions: Despite engaging distinct CD8⁺ TIL subsets and transcriptional programs, both Nivo+Rela and Nivo+Ipi
ultimately promoted functional TEM/TRM populations. These findings reveal regimen-specific immune mechanisms
underlying successful neoadjuvant ICI responses in HNSCC and inform rational design of future immunotherapeutic
strategies.

Acknowledgments and funding: This work was supported by NIH grants R01 DE031947 (to J.H.W., L.V. and R.L.F.),
R01 CA206517 (to R.L.F.), Head and Neck SPORE P50 CA097190-17 (to R.L.F.). The conduct of this trial was partially
supported by a grant from Bristol-Myers Squibb.

We would like to thank all the patients who participated in the study. We acknowledge the following HCC shared
resources (supported in part by NIH P30CA047904; R.L.F.): Flow Cytometry Facility and Cancer Genomics Facilities This
research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735,
through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number
S10OD028483.

L09
Dual blockage of PD-L/PD-1 and IL33/ST2 axes as a potential antitumor therapy

Ivan Jovanovic , Marina Jovanovic , David Geller , Nevena Gajovic , Milena Jurisevic , Nebojsa Arsenijevic , Milan
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Jovanovic , Gordana Supic , Danilo Vojvodic 3
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1 Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
2 Department of Surgery, University of Pittsburgh, USA
3 Medical Faculty of Military Medical Academy, University of Defense, Belgrade, Serbia
Keywords: breast cancer, antitumor immunity, PD1, IL-33
Background: Despite great advances in early diagnosis and treatment, breast cancer is still the leading cause of death
among women aged 35 to 54 years of age. Although radiotherapy, chemotherapy and surgery are options for treating
breast cancer, there has been an increase in the exploration of alternative treatments, such as immunotherapy. Our
goal was to examine how modulation of antitumor immunity affects breast tumor growth and progression. Although
separate blockage of either IL33/ST2 or PD-L/PD-1 axes has been shown to be beneficial in many tumors, co-blockage
of IL33/ST2 and PD-L/PD-1 has not been studied yet.
Material and Methods: 4T1 breast cancer and CT26 colon cancer were induced in BALB/C wild type (WT) and BALB/C
ST2 knockout mice, after which mice underwent anti PD-1 and anti IL-33 treatments.
Results: Co-blockage of IL33/ST2 and PD-L/PD-1 delayed tumor appearance and slowed tumor growth. Enhanced NK
cell cytotoxicity was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and STAT3,
increased expression of activation markers and decreased expression of immunosuppressive markers in splenic and
primary tumor-derived NK cells. Accumulation of immunosuppressive myeloid-derived suppressor cells and regulatory
T cells was significantly impaired in the spleen and primary tumor of ST2 knockout anti-PD-1-treated mice.
Conclusions: Co-blockage of IL3/ST2 and PD-L/PD-1 axes impedes tumor progression more efficiently than the single
blockage of either axis, thus offering a potential new approach to tumor immunotherapy.
Acknowledgments and funding: This work was supported by a grant from the Serbian Ministry of Education, Science
and Technological Development (175069), project with PR China (06/2018), from the Faculty of Medical Sciences,
University of Kragujevac (projects JP15/19 and JP11/18) and from the Project of Medical Faculty of Military Medical
Academy, Belgrade, Serbia, MFVMA/02/20-22, Serbia.

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