Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Funding Information: We are grateful for assistance from the Advanced Light Microscopy, Advanced Sequencing, Experimental Histopathology, Biological Research, Cell Services, Proteomics, Flow Cytometry and Scientific Computing facilities at the Francis Crick Institute. The TRACERx study (ClinicaTtrials.gov: NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent research ethics committee (13/LO/1546). TRACERx is funded by Cancer Research UK (C11496/A17786) and is coordinated through the Cancer Research UK and University College London Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study. We thank all site personnel, investigators, funders and industry partners who supported the generation of the data within this study. The results shown here are in whole or part based on data generated by the TCGA Research Network ( http://cancergenome.nih.gov ). The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. This work was supported by the Francis Crick Institute (CC2097, CC2088, CC2041 and CC2044), which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. This work was also supported by the Cancer Research UK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as by the University College London Experimental Cancer Medicine Centre. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 101018670). C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); the Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust and the Butterfield and Stoneygate Trusts; the Novo Nordisk Foundation (ID16584); the Royal Society Professorship Enhancement Award (RP/EA/180007); the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK–University College London Centre; the Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US); and the Mark Foundation for Cancer Research Aspire Award (grant no. 21-029-ASP). This work was supported by a Stand Up To Cancer–LUNGevity–American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). K.S.S.E. was supported by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 838540 and the Royal Society (RF\ERE\210216). A.F. has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 892360. S.d.C.T. was funded in part by a Marie Skłodowska-Curie Individual Fellowship from the European Union (MSCA-IF-2015-EF-ST 703228-iGEMMdev). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). S.-H.L. is supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HR20C0025), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (grant no. 2020R1A2C3006535). C.M.-R. is supported by the Rosetrees Trust (M630) and by the Wellcome Trust. A.M.F. is supported by Stand Up To Cancer (SU2C-AACR-DT23-17). M.A.B. is supported by Cancer Research UK and the Rosetrees Trust. K.L. is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), the Rosetrees Trust and Cotswold Trust (A2437), and Cancer Research UK (C69256/A30194). N.J.B. is a fellow of the Lundbeck Foundation (R272-2017-4040) and acknowledges funding from the Aarhus University Research Foundation (AUFF-E-2018-7-14) and the Novo Nordisk Foundation (NNF21OC0071483). N. McGranahan is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant no. 211179/Z/18/Z), and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals, and the Cancer Research UK–University College London Experimental Cancer Medicine Centre. M.J.-H. is a CRUK Career Establishment Awardee and has received funding from CRUK, the IASLC International Lung Cancer Foundation, the Lung Cancer Research Foundation, the Rosetrees Trust, UKI NETs, the NIHR and the NIHR UCLH Biomedical Research Centre. Funding Information: We are grateful for assistance from the Advanced Light Microscopy, Advanced Sequencing, Experimental Histopathology, Biological Research, Cell Services, Proteomics, Flow Cytometry and Scientific Computing facilities at the Francis Crick Institute. The TRACERx study (ClinicaTtrials.gov: NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent research ethics committee (13/LO/1546). TRACERx is funded by Cancer Research UK (C11496/A17786) and is coordinated through the Cancer Research UK and University College London Cancer Trials Centre, which has a core grant from CRUK (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study. We thank all site personnel, investigators, funders and industry partners who supported the generation of the data within this study. The results shown here are in whole or part based on data generated by the TCGA Research Network (http://cancergenome.nih.gov). The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. This work was supported by the Francis Crick Institute (CC2097, CC2088, CC2041 and CC2044), which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. This work was also supported by the Cancer Research UK Lung Cancer Centre of Excellence and the CRUK City of London Centre Award (C7893/A26233) as well as by the University College London Experimental Cancer Medicine Centre. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 101018670). C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); the Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust and the Butterfield and Stoneygate Trusts; the Novo Nordisk Foundation (ID16584); the Royal Society Professorship Enhancement Award (RP/EA/180007); the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK–University College London Centre; the Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US); and the Mark Foundation for Cancer Research Aspire Award (grant no. 21-029-ASP). This work was supported by a Stand Up To Cancer–LUNGevity–American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). K.S.S.E. was supported by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 838540 and the Royal Society (RF\ERE\210216). A.F. has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 892360. S.d.C.T. was funded in part by a Marie Skłodowska-Curie Individual Fellowship from the European Union (MSCA-IF-2015-EF-ST 703228-iGEMMdev). T.K. is supported by the JSPS Overseas Research Fellowships Program (202060447). S.-H.L. is supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HR20C0025), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (grant no. 2020R1A2C3006535). C.M.-R. is supported by the Rosetrees Trust (M630) and by the Wellcome Trust. A.M.F. is supported by Stand Up To Cancer (SU2C-AACR-DT23-17). M.A.B. is supported by Cancer Research UK and the Rosetrees Trust. K.L. is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), the Rosetrees Trust and Cotswold Trust (A2437), and Cancer Research UK (C69256/A30194). N.J.B. is a fellow of the Lundbeck Foundation (R272-2017-4040) and acknowledges funding from the Aarhus University Research Foundation (AUFF-E-2018-7-14) and the Novo Nordisk Foundation (NNF21OC0071483). N. McGranahan is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant no. 211179/Z/18/Z), and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals, and the Cancer Research UK–University College London Experimental Cancer Medicine Centre. M.J.-H. is a CRUK Career Establishment Awardee and has received funding from CRUK, the IASLC International Lung Cancer Foundation, the Lung Cancer Research Foundation, the Rosetrees Trust, UKI NETs, the NIHR and the NIHR UCLH Biomedical Research Centre. Publisher Copyright: © 2023, The Author(s).Peer reviewedPublisher PD

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy respons

Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic

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Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population

Antibodies against endogenous retroviruses promote lung cancer immunotherapy.

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer.

In this report from the CAPTURE study (NCT03226886), we demonstrate that a third dose of COVID-19 vaccine boosts neutralizing antibody (NAb) and cellular responses in patients with cancer, including those that had undetectable NAb titers (NAbT) following two vaccine doses or for whom NAbT waned. We have noted that one key member of the CAPTURE consortium—Sanjay Popat—was inadvertently not included in the author list. We now include him as a co-author. There are no additional changes to the declaration of interests statement, since Dr. Popat declares no competing conflict of interest. This author list change is now reflected in the online version of this letter