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Anti-4-1BB immunotherapy enhances systemic immune effects of radiotherapy to induce B and T cell-dependent anti-tumor immune activation and improve tumor control at unirradiated sites

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Abstract

Radiation therapy (RT) can prime and boost systemic anti-tumor effects via STING activation, resulting in enhanced tumor antigen presentation and antigen recognition by T cells. It is increasingly recognized that optimal anti-tumor immune responses benefit from coordinated cellular (T cell) and humoral (B cell) responses. However, the nature and functional relevance of the RT-induced immune response are controversial, beyond STING signaling, and agonistic interventions are lacking. Here, we show that B and CD4+ T cell accumulation at tumor beds in response to RT precedes the arrival of CD8+ T cells, and both cell types are absolutely required for abrogated tumor growth in non-irradiated tumors. Further, RT induces increased expression of 4-1BB (CD137) in both T and B cells; both in preclinical models and in a cohort of patients with small cell lung cancer treated with thoracic RT. Accordingly, the combination of RT and anti-41BB therapy leads to increased immune cell infiltration in the tumor microenvironment and significant abscopal effects. Thus, 4-1BB therapy enhances radiation-induced tumor-specific immune responses via coordinated B and T cell responses, thereby preventing malignant progression at unirradiated tumor sites. These findings provide a rationale for combining RT and 4-1bb therapy in future clinical trials.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work has been supported by K08 (5K08CA231454) Career Development Award supporting B.A.P.; and by R01CA124515 and R01CA240434 to JRCG. Support for Shared Resources was provided by Cancer Center Support Grant (CCSG) CA076292 to H. Lee Moffitt Cancer Center.

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Author notes

  1. Alexandra L. Martin and Chase Powell contributed equally to this work.

Authors and Affiliations

  1. Departments of Clinical Science, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Alexandra L. Martin & Chase Powell

  2. Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Mate Z. Nagy, Patrick Innamarato, John Powers, Derek Nichols, Carmen M. Anadon, Ricardo A. Chaurio, Sungjune Kim, Min-hsuan Wang, Jose R. Conejo-Garcia & Bradford A. Perez

  3. Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Sungjune Kim & Bradford A. Perez

  4. Compass Therapeutics, Boston, MA, 02135, USA

    Bing Gong, Xianzhe Wang & Thomas J. Scheutz

  5. Department of Thoracic Oncology, Center for Cancer Immunotherapy, Duke University Medical Center, Durham, 27712, USA

    Scott J. Antonia

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Alexandra Martin, Chase Powell, Derek Nichols, Pasquale Innamarato, Mate Nagy, Min-hsuan Wang, Bing Gong, Xianzhe Wang, Thomas Scheutz. The first draft of the manuscript was written by Alexandra Martin, Chase Powell, Sungjune Kim, Jose Conejo-Garcia and Bradford Perez. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bradford A. Perez.

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Competing Interests

B.A.P has research funding (Bristol Myers Squibb) and has served on advisory board (AstraZeneca, G1 Therapeutics); all outside the submitted work. S. J. A. has served on advisory boards for Bristol Myers Squibb, Celsius, Merck, Samyang Biopharma, AstraZeneca/Medimmune; Consultant: Bristol Myers Squibb, Celsius, Merck, Samyang Biopharma, AstraZeneca/Medimmune, CBMG, Memgen, RAPT, Venn, Achilles Therapeutics, GlaxoSmithKline, Amgen; Scientific advisory board: CBMG, Memgen, RAPT, Venn, Achilles Therapeutics, GlaxoSmithKline, Amgen. J.R.C.G. has stock options in Compass Therapeutics, Anixa Biosciences and Alloy Therapeutics. He also receives consulting fees from Leidos, Alloy Therapeutics and Radyus Research; has sponsored research with Anixa Biosciences; and patent applications with Compass Therapeutics and Anixa Biosciences; all outside the submitted work.

Ethics approval

Animals for this study were maintained by the Moffitt Cancer Center animal facility according to the Association for Assessment and Accreditation of Laboratory Animal Care and National Institute of Health (NIH) standards. All experiments were conducted according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) at the University of South Florida.

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Informed consent was obtained from all individual participants included in the study.

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Supplementary Information

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262_2022_3325_MOESM1_ESM.tif

Supplementary file1(Supplementary Figure 1 Radiation-induced changes in CD8+ T cells at irradiated tumor sites, spleen, and irradiated draining lymph nodes of mice. (A) Flow cytometry analysis demonstrating no change in antigen exposed CD8+CD44+ T cells as a percent of CD8+ T cells at the irradiated tumor site compared to unirradiated control cohort. (B) slight increase in CD8+CD44+ T cells as a percent of CD8+ T cells in the peripheral spleen (C) no change in CD8+CD44+ T cells as a percent of CD8+ T cells is observed in the irradiated draining lymph nodes in B16-OVA mouse model described in Figure 1A. (D) Flow cytometry analysis demonstrating no significant increase in peripheral blood antigen-exposed CD8+CD45RA- memory T cells as a percent of CD8+ T cells following RT in patients with small cell lung cancer receiving thoracic RT as described in Figure 2D. Paired T test analyses of patient samples performed to compare Pre-RT and Post-RT time points across the study cohort) (TIF 24441 KB)

262_2022_3325_MOESM2_ESM.tif

Supplementary file2 (Supplementary Figure 2 4-1BB upregulation in peripheral blood lymphocyte subsets following thoracic RT (A-left) Flow cytometry analyses demonstrating increased % of 4-1BB+ peripheral non-Treg (Treg=CD4+CD25+CD127-) CD4+ T cells as a percent of non-Treg CD4+ T cells after RT in a representative patient with extensive stage small cell lung cancer receiving thoracic RT on clinical trial as described in Figure 2D. (A-right) Composite flow cytometry analysis demonstrating significant absolute changes from baseline of 4-1BB+ peripheral non-Treg CD4+ T cells following RT following RT in patients with small cell lung cancer receiving thoracic RT as described in Figure 2D. (B-left) Flow cytometry analyses demonstrating no change in 4-1BB+ peripheral Tregs (CD4+CD25+CD127-) in a representative patient with extensive stage small cell lung cancer receiving thoracic RT on clinical trial as described in Figure 2D. (B-right) Composite analysis demonstrating no change from baseline of 4-1BB+ peripheral non-Treg CD4+ T cells following RT. (C-left) Flow cytometry analyses demonstrating no change in 4-1BB+ B cells in a patient with extensive stage small cell lung cancer receiving thoracic RT on clinical trial as described in Figure 2D. (C-right) Composite analysis demonstrating no change of 4-1BB+ peripheral B cells as a percent of total B cells following RT in patients with small cell lung cancer receiving thoracic RT as described in Figure 2D. (D-left) Flow cytometry analyses demonstrating no change in 4-1BB+ CD8+ T cells as a percent of total CD8+ T cells in a representative patient with extensive stage small cell lung cancer receiving thoracic RT on clinical trial as described in Figure 2D. (D-right) Composite analysis demonstrating no change of 4-1BB+ peripheral 4-1BB+ CD8+ T cells as a percent of total CD8+ T cells following RT in patients with small cell lung cancer receiving thoracic RT as described in Figure 2D. Paired T test analyses of patient samples performed to compare Pre-RT and Post-RT time points across the study cohort) (TIF 22774 KB)

262_2022_3325_MOESM3_ESM.tif

Supplementary file3 (Supplementary Figure 3 RT alone and RT with 4-1BB agonism control tumor growth at irradiated tumor sites. (A)B16-OVA tumor growth in right flank of untreated mice. (B) Tumor growth curve of irradiated flank tumors in mice receiving ablative RT as outlined in Figure 1A. (C) Tumor growth of irradiated flank tumors in mice receiving ablative RT with combination of CTX-471-AF. (D) Right flank tumor growth curves of untreated mice inoculated with 10^6 Lewis lung carcinoma (LLC) cells. (E) Tumor growth curve of irradiated tumor flanks of mice that received ablative (8Gy x 3) RT treatment directed at the right tumor flank. (F) Tumor growth curve of irradiated tumors of mice that received a combination of RT with CTX-471-AF) (TIF 10012 KB)

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Martin, A.L., Powell, C., Nagy, M.Z. et al. Anti-4-1BB immunotherapy enhances systemic immune effects of radiotherapy to induce B and T cell-dependent anti-tumor immune activation and improve tumor control at unirradiated sites. Cancer Immunol Immunother 72, 1445–1460 (2023). https://doi.org/10.1007/s00262-022-03325-y

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