Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer

Hang Su, Yimeng Wang, Sajid Khan, Yinan Huang, Zhenfei Yi, Na Zhu, Zhenghao Li, Feng Leng, Yanfen Chen, Lin Yang, Takaji Matsutani, Zhenghong Lin, Suping Zhang

Genome Instability & Disease ›› 2024, Vol. 5 ›› Issue (4) : 183-196. DOI: 10.1007/s42764-024-00134-8

Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer

Author information +
History +

Abstract

Immunotherapy has made remarkable progress within the past decade, but the role of B cells in tumor immunity remains unclear. Here, we show that the combination therapy of anti-PD-1 and TLR9 agonist significantly suppresses the growth of colon and lung tumors in syngeneic mouse models and induces B cell expansion in the tumor-draining lymph nodes and spleen. Using immunological repertoire high-throughput sequencing, we found that combination therapy significantly increased the richness and decreased clonality of B-cell receptors (BCR) with the latter being inversely correlated with the efficacy of tumor inhibition. Moreover, secretory tumor-specific antibodies were increased in combination therapy and elicited Fc-directed tumor lysis function. Employing high-throughput single-cell BCR sequencing technology, we discovered a tumor specific monoclonal antibody (mAb), named 19C5, that had potent anti-tumor activity in vivo. Immunoprecipitation and mass spectrometry analysis revealed that 19C5 mAb specifically recognizes a tumor-associated antigen G protein pathway suppressor 1 (GPS1), whose expression is associated with a worse prognosis in human colon and lung cancer. Taken together, our data highlight the pivotal role of B cells and the production of tumor-reactive antibodies during immunotherapy, suggesting that dynamic changes to the BCR repertoire might serve as a biomarker to predict a clinical response for immunotherapy. We also provide a novel strategy to develop anti-tumor antibodies that may target tumor-associated antigens.

Keywords

B-cell receptor repertoire / Immunotherapy / Monoclonal antibody / Clonality

Cite this article

Download citation ▾
Hang Su, Yimeng Wang, Sajid Khan, Yinan Huang, Zhenfei Yi, Na Zhu, Zhenghao Li, Feng Leng, Yanfen Chen, Lin Yang, Takaji Matsutani, Zhenghong Lin, Suping Zhang. Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer. Genome Instability & Disease, 2024, 5(4): 183‒196 https://doi.org/10.1007/s42764-024-00134-8

References

[]
Agrawal S, Kandimalla ER. Intratumoural immunotherapy: Activation of nucleic acid sensing pattern recognition receptors. Immuno-oncology Technology, 2019, 3: 15-23, pmcid: 9216656
CrossRef Pubmed Google scholar
[]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A cancer Journal for Clinicians, 2018, 68(6): 394-424,
CrossRef Pubmed Google scholar
[]
Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, et al.. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature, 2020, 577(7791): 561-565,
CrossRef Pubmed Google scholar
[]
Corbière V, Chapiro J, Stroobant V, Ma W, Lurquin C, Lethé B, van Baren N, Van den Eynde BJ, Boon T, Coulie PG. (2011). Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer research, 71(4), 1253–1262. https://doi.org/10.1158/0008-5472.can-10-2693
[]
Cyster JG, Allen CDC. B cell responses: Cell Interaction dynamics and decisions. Cell, 2019, 177(3): 524-540, pmcid: 6538279
CrossRef Pubmed Google scholar
[]
Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nature Reviews. Clinical Oncology, 2017, 14(12): 717-734,
CrossRef Pubmed Google scholar
[]
Gallotta M, Assi H, Degagné É, Kannan SK, Coffman RL, Guiducci C. Inhaled TLR9 agonist renders lung tumors permissive to PD-1 blockade by promoting optimal CD4(+) and CD8(+) T-cell interplay. Cancer Research, 2018, 78(17): 4943-4956,
CrossRef Pubmed Google scholar
[]
Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, Diaz LA Jr. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nature Reviews Gastroenterology & Hepatology, 2019, 16(6): 361-375,
CrossRef Google scholar
[]
Greiff V, Menzel U, Miho E, Weber C, Riedel R, Cook S, Valai A, Lopes T, Radbruch A, Winkler TH. Systems analysis reveals high genetic and antigen-driven predetermination of antibody repertoires throughout B cell development. Cell Reports, 2017, 19(7): 1467-1478,
CrossRef Pubmed Google scholar
[]
GuhaThakurta D, Sheikh NA, Fan LQ, Kandadi H, Meagher TC, Hall SJ, Kantoff PW, Higano CS, Small EJ, Gardner TA et al. (2015). Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome. Clinical cancer research: an official journal of the American Association for Cancer Research, 21(16), 3619–3630. https://doi.org/10.1158/1078-0432.ccr-14-2334
[]
Gulley, J. L., Madan, R. A., Pachynski, R., Mulders, P., Sheikh, N. A., Trager, J., & Drake, C. G. (2017). Role of Antigen Spread and distinctive characteristics of Immunotherapy in Cancer Treatment. Journal of the National Cancer Institute, 109(4). https://doi.org/10.1093/jnci/djw261
[]
Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, et al.. B cells and tertiary lymphoid structures promote immunotherapy response. Nature, 2020, 577(7791): 549-555, pmcid: 8762581
CrossRef Pubmed Google scholar
[]
Kim SS, Sumner WA, Miyauchi S, Cohen EEW, Califano JA, Sharabi AB. Role of B cells in responses to checkpoint blockade immunotherapy and overall survival of Cancer patients. Clinical cancer Research: An Official Journal of the American Association for Cancer Research, 2021, 27(22): 6075-6082,
CrossRef Pubmed Google scholar
[]
Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Reviews Immunology, 2004, 4(4): 249-258,
CrossRef Pubmed Google scholar
[]
Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, Jeng YM, Hsiao LP, Lacroix L, Bougoüin A, et al.. B cells are associated with survival and immunotherapy response in sarcoma. Nature, 2020, 577(7791): 556-560,
CrossRef Pubmed Google scholar
[]
Postow MA, Manuel M, Wong P, Yuan J, Dong Z, Liu C, Perez S, Tanneau I, Noel M, Courtier A, et al.. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. Journal for Immunotherapy of cancer, 2015, 3: 23, pmcid: 4469400
CrossRef Pubmed Google scholar
[]
Ribas A, Medina T, Kummar S, Amin A, Kalbasi A, Drabick JJ, Barve M, Daniels GA, Wong DJ, Schmidt EV, et al.. SD-101 in combination with Pembrolizumab in Advanced Melanoma: Results of a phase ib, Multicenter Study. Cancer Discovery, 2018, 8(10): 1250-1257, pmcid: 6719557
CrossRef Pubmed Google scholar
[]
Robert L, Tsoi J, Wang X, Emerson R, Homet B, Chodon T, Mok S, Huang RR, Cochran AJ, Comin-Anduix B, et al.. CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clinical cancer Research: An Official Journal of the American Association for Cancer Research, 2014, 20(9): 2424-2432,
CrossRef Pubmed Google scholar
[]
Schleimann MH, Kobberø ML, Vibholm LK, Kjær K, Giron LB, Busman-Sahay K, Chan CN, Nekorchuk M, Schmidt M, Wittig B, et al.. TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes. EBioMedicine, 2019, 45: 328-340, pmcid: 6642412
CrossRef Pubmed Google scholar
[]
Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, et al.. Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: Identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR. Journal of neuro-oncology, 2008, 88(3): 281-291,
CrossRef Pubmed Google scholar
[]
Snyder A, Nathanson T, Funt SA, Ahuja A, Buros Novik J, Hellmann MD, Chang E, Aksoy BA, Al-Ahmadie H, Yusko E, et al.. Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. PLoS Medicine, 2017, 14(5): e1002309, pmcid: 5446110
CrossRef Pubmed Google scholar
[]
Soria JC, Marabelle A, Brahmer JR, Gettinger S. Immune checkpoint modulation for non-small cell lung cancer. Clinical cancer Research: An Official Journal of the American Association for Cancer Research, 2015, 21(10): 2256-2262,
CrossRef Pubmed Google scholar
[]
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al.. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 2014, 515(7528): 568-571, pmcid: 4246418
CrossRef Pubmed Google scholar
[]
Wang S, Campos J, Gallotta M, Gong M, Crain C, Naik E, Coffman RL, Guiducci C. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8 + T cells. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(46): E7240-e7249, pmcid: 5135381
CrossRef Pubmed Google scholar
[]
Wei H, Niu Z, Ji R, Jiang W, Tang J, Meng Z, Cao X, Zhang X, Liu X. Bioinformatics analysis of GPS1 expression and biological function in breast cancer. Journal of cancer Research and Clinical Oncology, 2024, 150(2): 52, pmcid: 10827974
CrossRef Pubmed Google scholar
[]
Xu JL, Davis MM. Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity, 2000, 13(1): 37-45,
CrossRef Pubmed Google scholar
[]
Yoshida R, Yoshioka T, Yamane S, Matsutani T, Toyosaki-Maeda T, Tsuruta Y, Suzuki R. A new method for quantitative analysis of the mouse T-cell receptor V region repertoires: Comparison of repertoires among strains. Immunogenetics, 2000, 52(1–2): 35-45,
CrossRef Pubmed Google scholar
Funding
National Natural Science Foundation of China(32170712); China Postdoctoral Science Foundation(2019M663093); Prevention and Control of COVID-2019 Research Program in University of Guangdong Province(2020KZDZX1176); Shenzhen Medical Research Fund(B2302022)

Accesses

Citations

Detail

Sections
Recommended

/