Peripheral B-cell levels predict efficacy and overall survival in advanced melanoma patients under PD-1 immunotherapy

Papers of special note have been highlighted as: • of interest

References

• 1. Betof Warner A, Palmer JS, Shoushtari AN et al. Long-term outcomes and responses to retreatment in patients with melanoma treated with PD-1 blockade. J. Clin. Oncol. 38(15), 1655–1663 (2020).
  MedlineGoogle Scholar
• 2. Bai X, Shoushtari AN, Betof Warner A et al. Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study. Br. J. Dermatol. 187(3), 401–410 (2022).
  Medline CASGoogle Scholar
• 3. Garutti M, Bonin S, Buriolla S et al. Find the flame: predictive biomarkers for immunotherapy in melanoma. Cancers 13(8), 1819 (2021).
  Medline CASGoogle Scholar
• 4. Reck M, Rodríguez-Abreu D, Robinson AG et al. KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375(19), 1823–1833 (2016).
  Medline CASGoogle Scholar
• 5. Ding W, LaPlant BR, Call TG et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 129(26), 3419–3427 (2017).
  Medline CASGoogle Scholar
• 6. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377(25), 2500–2501 (2017).
  MedlineGoogle Scholar
• 7. Ricciuti B, Wang X, Alessi JV et al. Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA. Oncol. 8(8), 1160–1168 (2022).
  MedlineGoogle Scholar
• 8. Gettinger SN, Choi J, Mani N et al. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat. Commun. 9(1), 3196 (2018).
  Medline CASGoogle Scholar
• 9. Nabet BY, Esfahani MS, Moding EJ et al. Noninvasive early identification of therapeutic benefit from immune checkpoint inhibition. Cell 183(2), 363–376.e13 (2020).
  Medline CASGoogle Scholar
• 10. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet 398(10304), 1002–1014 (2021).
  Medline CASGoogle Scholar
• 11. Garg K, Maurer M, Griss J et al. Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome. Hum. Pathol. 54, 157–64 (2016).
  Medline CASGoogle Scholar
• 12. Griss J, Bauer W, Wagner C et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10(1), 4186 (2019).
  MedlineGoogle Scholar
• 13. Schwartz LH, Litière S, de Vries E et al. RECIST 1.1 – update and clarification: from the RECIST Committee. Eur. J. Cancer 62, 132–7 (2016).
  MedlineGoogle Scholar
• 14. Huang H, Peng L, Zhang B et al. Combination of low-dose gemcitabine and PD-1 inhibitors for treatment in patients with advanced malignancies. Front. Immunol. 13, 882172 (2022).
  Medline CASGoogle Scholar
• 15. Willsmore ZN, Harris RJ, Crescioli S et al. B cells in patients with melanoma: implications for treatment with checkpoint inhibitor antibodies. Front. Immunol. 11, 622442 (2021).
  MedlineGoogle Scholar
• 16. Yuan S, Liu Y, Till B et al. Pretreatment peripheral B cells are associated with tumor response to anti-PD-1-Based Immunotherapy. Front. Immunol. 11, 563653 (2020).
  Medline CASGoogle Scholar
• 17. Damsky W, Jilaveanu L, Turner N et al. B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors. J. Immunother. Cancer 7(1), 153 (2019).
  MedlineGoogle Scholar
• 18. Martinez-Rodriguez M, Thompson AK, Monteagudo C. A significant percentage of CD20-positive TILs correlates with poor prognosis in patients with primary cutaneous malignant melanoma. Histopathology 65(5), 726–8 (2014).
  MedlineGoogle Scholar
• 19. Rodgers CB, Mustard CJ, McLean RT et al. A B-cell or a key player? The different roles of B-cells and antibodies in melanoma. Pigment Cell Melanoma Res. 35(3), 303–319 (2022).
  Medline CASGoogle Scholar
• 20. Yuan S, Hu X, Zhao Y et al. Case report: PD-1 inhibitor is active in lung adenocarcinoma with B cell deficiency. Front. Immunol. 11, 563622 (2022).
  Google Scholar
• 21. Wulfken LM, Becker JC, Hayajneh R et al. Case report: sustained remission due to PD-1-inhibition in a metastatic melanoma patient with depleted B cells. Front. Immunol. 12, 733961 (2021).
  Medline CASGoogle Scholar
• 22. Wang Z, Liu Y, Peng L et al. Role of fibrosarcoma-induced CD11b⁺ myeloid cells and tumor necrosis factor-α in B cell responses. Oncogene 41(10), 1434–1444 (2022).
  Medline CASGoogle Scholar
• 23. Hardy-Werbin M, Rocha P, Arpi O et al. Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer. Oncoimmunology. 8(6), e1593810 (2019).
  MedlineGoogle Scholar
• 24. Boutsikou E, Domvri K, Hardavella G et al. Tumour necrosis factor, interferon-gamma and interleukins as predictive markers of antiprogrammed cell-death protein-1 treatment in advanced non-small cell lung cancer: a pragmatic approach in clinical practice. Ther. Adv. Med. Oncol. 10, 1758835918768238 (2018).
  Google Scholar
• 25. Sanmamed MF, Perez-Gracia JL, Schalper KA et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann. Oncol. 28(8), 1988–1995 (2017).
  Medline CASGoogle Scholar
• 26. Weide B, Martens A, Hassel JC et al. Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab. Clin. Cancer Res. 22(22), 5487–5496 (2016).
  Medline CASGoogle Scholar
• 27. Mezquita L, Auclin E, Ferrara R et al. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer. JAMA. Oncol. 4(3), 351–357 (2018).
  MedlineGoogle Scholar
• 28. Capone M, Giannarelli D, Mallardo D et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J. Immunother. Cancer 6(1), 74 (2018).
  MedlineGoogle Scholar
• 29. Kaufman HL, Russell JS, Hamid O et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J. Immunother. Cancer 6(1), 7 (2018).
  MedlineGoogle Scholar
• 30. Ferrucci PF, Ascierto PA, Pigozzo J et al. Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann. Oncol. 27(4), 732–8 (2016).
  Medline CASGoogle Scholar
• 31. Kitano S, Postow MA, Ziegler CG et al. Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol. Res. 2(8), 812–21 (2014).
  Medline CASGoogle Scholar
• 32. Martens A, Wistuba-Hamprecht K, Geukes Foppen M et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22(12), 2908–18 (2016).
  Medline CASGoogle Scholar
• 33. Gebhardt C, Sevko A, Jiang H et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin. Cancer Res. 21(24), 5453–9 (2015).
  Medline CASGoogle Scholar
• 34. Meyer C, Cagnon L, Costa-Nunes CM et al. Frequencies of circulating myeloid-derived suppressor cells correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63(3), 247–57 (2014).
  Medline CASGoogle Scholar
• 35. Retseck J, Nasr A, Lin Y et al. Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma. J. Transl. Med. 16(1), 184 (2018).
  Medline CASGoogle Scholar
• 36. Cader FZ, Hu X, Goh WL et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat. Med. 26(9), 1468–1479 (2020).
  Medline CASGoogle Scholar
• 37. Weide B, Martens A, Hassel JC et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin. Cancer. Res. 22(22), 5487–5496 (2016).
  Medline CASGoogle Scholar
• 38. Wang L, Simons DL, Lu X et al. Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer. Nat. Immunol. 20(9), 1220–1230 (2019).
  Medline CASGoogle Scholar
• 39. Cader FZ, Hu X, Goh WL et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat. Med. 26(9), 1468–1479 (2020).
  Medline CASGoogle Scholar
• 40. Yuan S, Liu Y, Till B et al. Pretreatment peripheral B cells are associated with tumor response to anti-PD-1-based immunotherapy. Front. Immunol. 11, 563653 (2020). • This paper shows that patients who develop progressive disease after therapy have a higher number of B cells than those achieving stable disease and partial response.
  Medline CASGoogle Scholar
• 41. Audenet F, Farkas AM, Anastos H et al. Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer. World J. Urol. 36(11), 1741–1748 (2018).
  Medline CASGoogle Scholar
• 42. Han J, Duan J, Bai H et al. TCR repertoire diversity of peripheral PD-1⁺CD8⁺ T Cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer. Cancer Immunol. Res. 8(1), 146–154 (2020).
  Medline CASGoogle Scholar
• 43. Griss J, Bauer W, Wagner C et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10(1), 4186 (2019).
  MedlineGoogle Scholar
• 44. Miyake M, Tatsumi Y, Gotoh D et al. Regulatory T cells and tumor-associated macrophages in the tumor microenvironment in non-muscle invasive bladder cancer treated with intravesical bacille Calmette-Guérin: a long-term follow-up study of a Japanese cohort. Int. J. Mol. Sci. 18(10), 2186 (2017).
  MedlineGoogle Scholar
• 45. Tumeh PC, Harview CL, Yearley JH et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528), 568–71 (2014).
  Medline CASGoogle Scholar
• 46. Wouters MCA, Nelson BH. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 24(24), 6125–6135 (2018).
  Medline CASGoogle Scholar
• 47. Tumeh PC, Harview CL, Yearley JH et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528), 568–71 (2014).
  Medline CASGoogle Scholar
• 48. Petitprez F, de Reyniès A, Keung EZ et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577(7791), 556–560 (2010). • This paper shows that B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents.
  Google Scholar
• 49. Cabrita R, Lauss M, Sanna A et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577(7791), 561–565 (2020). • Co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables.
  Medline CASGoogle Scholar
• 50. Helmink BA, Reddy SM, Gao J et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577(7791), 549–555 (2020). • Tertiary lymphoid structures containing B, T and follicular dendritic cells are predictive of response to immune checkpoint inhibitors.
  Medline CASGoogle Scholar
• 51. Rooney MS, Shukla SA, Wu CJ et al. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1–2), 48–61 (2015).
  Medline CASGoogle Scholar
• 52. Takada K, Shimokawa M, Takamori S et al. Clinical impact of probiotics on the efficacy of anti-PD-1 monotherapy in patients with nonsmall cell lung cancer: a multicenter retrospective survival analysis study with inverse probability of treatment weighting. Int. J. Cancer. 149(2), 473–482 (2021).
  Medline CASGoogle Scholar
• 53. Georgoulias G, Zaravinos A. Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden. Front. Immunol. 13, 1006665 (2022).
  Medline CASGoogle Scholar
• 54. Roufas C, Georgakopoulos-Soares I, Zaravinos A. Distinct genomic features across cytolytic subgroups in skin melanoma. Cancer Immunol. Immunother. 70(11), 3137–3154 (2021). • Cytolytic-high skin melanomas are significantly enriched for immune-related gene sets linked with activated CD8+ T cells, B cells, M1 macrophages, activated dendritic cells and NK cells.
  Medline CASGoogle Scholar
• 55. Georgoulias G, Zaravinos A. Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden. Front. Immunol. 13, 1006665 (2022). • High expression of most immunoreceptors is associated with the tumor-infiltrating lymphocyte load and patient survival but not with the tumor mutation burden.
  Medline CASGoogle Scholar