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01-12-2021 | Checkpoint Inhibitors | Review

Intersection of FcγRIIB, the microbiome, and checkpoint inhibitors in antitumor immunity

Authors: Kirsten M. Baecher, Mandy L. Ford

Published in: Cancer Immunology, Immunotherapy | Issue 12/2021

Abstract

Fc receptors (FcRs) and the microbiome are both known to have an effect on the development and progression of cancers. Checkpoint inhibitors are a novel class of therapeutics which are used to combat cancer and are integrally linked to both FcRs and the microbiome. The use of checkpoint inhibitors has grown exponentially over the past decade, although many host factors affect both the efficacy and the safety of these therapeutics. Some of these host factors, including the microbiome and the expression of FcRs, are currently being investigated. Here we discuss the current understanding of FcRs (particularly the inhibitory FcγRIIB) and the microbiome in context of T cell immunity, inflammation, cancer, and checkpoint inhibition.

Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18(3):153–167. https://doi.org/10.1038/nri.2017.108CrossRefPubMed

Guo Q, Huang F, Goncalves C, Del Rincon SV, Miller WH Jr (2019) Translation of cancer immunotherapy from the bench to the bedside. Adv Cancer Res 143:1–62. https://doi.org/10.1016/bs.acr.2019.03.001CrossRefPubMed

Schildberg FA, Klein SR, Freeman GJ, Sharpe AH (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44(5):955–972. https://doi.org/10.1016/j.immuni.2016.05.002CrossRefPubMedPubMedCentral

Rausch MP, KT H (2017) Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application. Ward WH, Farma JM, editors Cutaneous Melanoma: Etiology and Therapy [Internet] Brisbane (AU): Codon Publications; 2017 Dec 21 Chapter 9. doi:https://doi.org/10.15586/codon.cutaneousmelanoma.2017.ch9

Esfahani K, Roudaia L, Buhlaiga N, Del Rincon SV, Papneja N, Miller WH Jr (2020) A review of cancer immunotherapy: from the past, to the present, to the future. Current oncology (Toronto, Ont) 27(Suppl 2):S87–S97. https://doi.org/10.3747/co.27.5223CrossRef

Testori AAE, Ribero S, Indini A, Mandalà M (2019) Adjuvant treatment of melanoma: recent developments and future perspectives. Am J Clin Dermatol 20(6):817–827. https://doi.org/10.1007/s40257-019-00456-4CrossRefPubMed

Rao SV, Moran AE, Graff JN (2017) Predictors of response and resistance to checkpoint inhibitors in solid tumors. Ann Transl Med 5(23):468CrossRefPubMedPubMedCentral

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239CrossRefPubMedPubMedCentral

Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894. https://doi.org/10.1200/jco.2014.56.2736CrossRefPubMedPubMedCentral

10.

Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(6382):1350–1355. https://doi.org/10.1126/science.aar4060CrossRefPubMedPubMedCentral

11.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356. https://doi.org/10.1056/NEJMoa1709684CrossRefPubMedPubMedCentral

12.

Hayes JM, Cosgrave EFJ, Struwe WB, Wormald M, Davey GP, Jefferis R, Rudd PM (2014) Glycosylation and Fc Receptors. In: Daeron M, Nimmerjahn F (eds) Fc Receptors. Springer International Publishing, Cham, pp 165–199CrossRef

13.

van Tetering G, Evers M, Chan C, Stip M, Leusen J (2020) Fc engineering strategies to advance iga antibodies as therapeutic agents. Antibodies 9(4):70CrossRefPubMedCentral

14.

van der Poel CE, Spaapen RM, van de Winkel JG, Leusen JH (2011) Functional characteristics of the high affinity IgG receptor. FcγRI J Immunol 186(5):2699–2704. https://doi.org/10.4049/jimmunol.1003526CrossRefPubMed

15.

Nimmerjahn F, Ravetch JV (2006) Fcgamma receptors: old friends and new family members. Immunity 24(1):19–28. https://doi.org/10.1016/j.immuni.2005.11.010CrossRefPubMed

16.

Nimmerjahn F, Ravetch JV (2008) Fcγ receptors as regulators of immune responses. Nat Rev Immunol 8(1):34–47. https://doi.org/10.1038/nri2206CrossRefPubMed

17.

Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV (2015) FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 28(3):285–295. https://doi.org/10.1016/j.ccell.2015.08.004CrossRefPubMed

18.

Smith KGC (2010) Clatworthy MR (2010) FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 10(5):328–343. https://doi.org/10.1038/nri2762CrossRefPubMedPubMedCentral

19.

Jensen WA, Marschner S, Ott VL (2001) Cambier JC (2001) FcgammaRIIB-mediated inhibition of T-cell receptor signal transduction involves the phosphorylation of SH2-containing inositol 5-phosphatase (SHIP), dephosphorylation of the linker of activated T-cells (LAT) and inhibition of calcium mobilization. Biochem Soc Trans 29(Pt 6):840–846. https://doi.org/10.1042/0300-5127:0290840CrossRefPubMed

20.

Starbeck-Miller GR, Badovinac VP, Barber DL, Harty JT (2014) Cutting edge: expression of FcγRIIB tempers memory CD8 T cell function in vivo. J Immunol 192(1):35–39. https://doi.org/10.4049/jimmunol.1302232CrossRefPubMed

21.

Morris AB, Farley CR, Pinelli DF, Adams LE, Cragg MS, Boss JM, Scharer CD, Fribourg M, Cravedi P, Heeger PS, Ford ML (2020) Signaling through the inhibitory Fc receptor FcγRIIB induces CD8(+) T cell apoptosis to limit T cell immunity. Immunity 52(1):136-150.e136. https://doi.org/10.1016/j.immuni.2019.12.006CrossRefPubMedPubMedCentral

22.

Su K, Yang H, Li X, Li X, Gibson AW, Cafardi JM, Zhou T, Edberg JC, Kimberly RP (2007) Expression profile of FcgammaRIIb on leukocytes and its dysregulation in systemic lupus erythematosus. J Immunol 178(5):3272–3280. https://doi.org/10.4049/jimmunol.178.5.3272CrossRefPubMed

23.

Castro-Dopico T, Clatworthy MR (2019) IgG and Fcγ receptors in intestinal immunity and inflammation. Front Immunol. https://doi.org/10.3389/fimmu.2019.00805CrossRefPubMedPubMedCentral

24.

Cassard L, Cohen-Solal J, Camilleri-Broët S, Fournier E, Fridman WH, Sautès-Fridman C (2006) Fc gamma receptors and cancer. Springer Semin Immun 28(28):321–328. https://doi.org/10.1007/s00281-006-0058-8CrossRef

25.

Teige I, Mårtensson L, Frendéus BL (2019) Targeting the antibody checkpoints to enhance cancer immunotherapy-focus on FcγRIIB. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2019.00481CrossRefPubMedPubMedCentral

26.

Luo Y, Lu Z, Raso SW, Entrican C, Tangarone B (2009) Dimers and multimers of monoclonal IgG1 exhibit higher in vitro binding affinities to Fcgamma receptors. MAbs 1(5):491–504. https://doi.org/10.4161/mabs.1.5.9631CrossRefPubMedPubMedCentral

27.

Bournazos S, Wang TT, Ravetch JV (2016) The Role and function of Fcγ receptors on myeloid cells. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.MCHD-0045-2016CrossRefPubMed

28.

Ono M, Bolland S, Tempst P, Ravetch JV (1996) Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature 383(6597):263–266. https://doi.org/10.1038/383263a0CrossRefPubMed

29.

Famiglietti SJ, Nakamura K, Cambier JC (1999) Unique features of SHIP, SHP-1 and SHP-2 binding to FcgammaRIIb revealed by surface plasmon resonance analysis. Immunol Lett 68(1):35–40. https://doi.org/10.1016/s0165-2478(99)00027-9CrossRefPubMed

30.

Xu Z, Liu L, Cui Z, Bi K, Zhang N, Zhang Y, Liu Z (2018) The Unique inhibitory IgG receptor–FcγRIIb. Protein Pept Lett 25(11):966–972. https://doi.org/10.2174/0929866525666181026162216CrossRefPubMed

31.

Espeli M, Smith KGC, Clatworthy MR (2016) FcγRIIB and autoimmunity. Immunol Rev. https://doi.org/10.1111/imr.12368CrossRefPubMed

32.

Liu W, Won Sohn H, Tolar P, Meckel T, Pierce SK (2010) Antigen-induced oligomerization of the B cell receptor is an early target of Fc gamma RIIB inhibition. J Immunol 184(4):1977–1989. https://doi.org/10.4049/jimmunol.0902334CrossRefPubMed

33.

Tzeng SJ, Bolland S, Inabe K, Kurosaki T, Pierce SK (2005) The B cell inhibitory Fc receptor triggers apoptosis by a novel c-Abl family kinase-dependent pathway. J Biol Chem 280(42):35247–35254. https://doi.org/10.1074/jbc.M505308200CrossRefPubMed

34.

Farley CR, Morris AB, Tariq M, Bennion KB, Potdar S, Kudchadkar R, Lowe MC, Ford ML (2021) FcγRIIB is a T cell checkpoint in antitumor immunity. JCI Insight. https://doi.org/10.1172/jci.insight.135623CrossRefPubMedPubMedCentral

35.

Lu J, Mold C, Clos TWD, Sun PD (2018) Pentraxins and Fc receptor-mediated immune responses. Front Immunol 9:2607. https://doi.org/10.3389/fimmu.2018.02607CrossRefPubMedPubMedCentral

36.

Jimenez RV, Wright TT, Jones NR, Wu J, Gibson AW, Szalai AJ (2018) C-reactive protein impairs dendritic cell development, maturation, and function: implications for peripheral tolerance. Front Immunol 9:372. https://doi.org/10.3389/fimmu.2018.00372CrossRefPubMedPubMedCentral

37.

Zhang L, Liu SH, Wright TT, Shen ZY, Li HY, Zhu W, Potempa LA, Ji SR, Szalai AJ, Wu Y (2015) C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. J Immunol 194(11):5243–5252. https://doi.org/10.4049/jimmunol.1402909CrossRefPubMed

38.

Chen X, Song X, Li K, Zhang T (2019) FcγR-binding is an important functional attribute for immune checkpoint antibodies in cancer immunotherapy. Front Immunol 10:292. https://doi.org/10.3389/fimmu.2019.00292CrossRefPubMedPubMedCentral

39.

Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, Weissleder R, Pittet MJ (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aal3604CrossRefPubMedPubMedCentral

40.

Vargas FA, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Rota EM, Dahan R, Georgiou A, Sledzinska A, Aissa AB, Franz D, Sunderland MW, Wong YNS, Henry JY, O'Brien T, Nicol D, Challacombe B, Beers SA, Consortium MT, Consortium RT, Consortium LT, Turajlic S, Gore M, Larkin J, Swanton C, Chester KA, Pule M, Ravetch JV, Marafioti T, Peggs KS, Quezada SA (2017) Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes With PD-1 Blockade to Eradicate Established Tumors. Immunity

41.

Vargas FA, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon s, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Aissa AB, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B, Renal TMT, consortia TL, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, Quezada1 SA (2018) Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer Cell 33:649-663. doi:doi: https://doi.org/10.1016/j.ccell.2018.02.010

42.

Morris AB, Farley CR, Pinelli DF, Cravedi P, Heeger PS, Ford ML (2019) Signaling through the inhibitory Fc receptor FcgRIIB induces CD8 T cell apoptosis to limit T cell immunity. Immunity 52(1):136–150CrossRef

43.

Zitvogel L, Daillère R, Roberti MP, Routy B, Kroemer G (2017) Anticancer effects of the microbiome and its products. Nature. https://doi.org/10.1038/nrmicro.2017.44CrossRef

44.

Dai Z, Zhang J, QiWu CJ, Liu J, Wang L, Chen C, Xu J, Zhang H, Shi C, Li Z, Fang H, Lin C, Tang D, Wang D (2018) The role of microbiota in the development of colorectal cancer. Int J Cancer 145:2032–2041CrossRef

45.

Mkaddem SB, Benhamou M, Monteiro RC (2019) Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools. Front Immunol 10:811. https://doi.org/10.3389/fimmu.2019.00811CrossRefPubMedPubMedCentral

46.

Breedveld A, Mv E (2019) IgA and FcαRI: pathological roles and therapeutic opportunities. Front Immunol 10:553. https://doi.org/10.3389/fimmu.2019.00553CrossRefPubMedPubMedCentral

47.

Rogier EW, Frantz AL, Bruno ME, Wedlund L, Cohen DA, Stromberg AJ, Kaetzel CS (2014) Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proc Natl Acad Sci U S A 111(8):3074–3079. https://doi.org/10.1073/pnas.1315792111CrossRefPubMedPubMedCentral

48.

Kaetzel CS (2014) Cooperativity among secretory IgA, the polymeric immunoglobulin receptor, and the gut microbiota promotes host-microbial mutualism. Immunol Lett 162:10–21CrossRefPubMedPubMedCentral

49.

Zheng D, Liwinski T, Elinav E (2020) Interaction between microbiota and immunity in health and disease. Cell Res 30(6):492–506. https://doi.org/10.1038/s41422-020-0332-7CrossRefPubMedPubMedCentral

50.

Zhang Z, Tang H, Chen P, Xie H, Tao Y (2019) Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome. Signal Transduct Target Ther 4:41. https://doi.org/10.1038/s41392-019-0074-5CrossRefPubMedPubMedCentral

51.

Bachem A, Makhlouf C, Binger KJ, Souza DPd, Tull D, Hochheiser K, Whitney PG, Fernandez-Ruiz D, Dähling S, Kastenmüller W, Jönsson J, Gressier E, Lew AM, Perdomo C, Kupz A, Figgett W, Mackay F, Oleshansky M, Russ BE, Parish IA, Kallies A, McConville MJ, Turner SJ, Gebhardt T, Bedoui S (2019) Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8 + T Cells. Immunity 51(2):285-297.e5. https://doi.org/10.1016/j.immuni.2019.06.002CrossRefPubMed

52.

Fenton SE, Sosman JA, Chandra S (2019) Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors. Cancer Drug Resistance 2(3):744–761. https://doi.org/10.20517/cdr.2019.28CrossRef

53.

Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264):1079–1084. https://doi.org/10.1126/science.aad1329CrossRefPubMedPubMedCentral

54.

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Macedo MPd, Cotechini T, Kumar T, Chen WS, Reddy SM, Sloane RS, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, E. Marcelo Riquelme Sanchez, Zhang Y, Chatelier EL, Zitvogel L, Pons N, J. L. Austin-Breneman, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Z. A. Cooper, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA (2018) Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science 2018 Jan 5; 359(6371): 97–103. doi:https://doi.org/10.1126/science.

55.

Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, Vaysse T, Marthey L, Eggermont A, Asvatourian V, Lanoy E, Mateus C, Robert C, Carbonnel F (2017) Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 28(6):1368–1379. https://doi.org/10.1093/annonc/mdx108CrossRefPubMed

56.

Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264):1084–1089. https://doi.org/10.1126/science.aac4255CrossRefPubMedPubMedCentral

57.

Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ (2018) Gajewski TF (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359(6371):104–108. https://doi.org/10.1126/science.aao3290CrossRefPubMedPubMedCentral

Title: Intersection of FcγRIIB, the microbiome, and checkpoint inhibitors in antitumor immunity
Authors: Kirsten M. Baecher
Mandy L. Ford
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keyword: Checkpoint Inhibitors
Published in: Cancer Immunology, Immunotherapy / Issue 12/2021
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-021-03004-4

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