Immunotherapy and Cancer

Fridman WH, Kourilsky FM. Stimulation of lymphocytes by autologous leukaemic cells in acute leukaemia. Nature. 1969 Oct 18;224(5216):277-9. doi: 10.1038/224277a0. PMID: 5259376. Read

Demonstration that the immune system of a patient could recognize its own cancer cells and be activated to initiate an anti-tumor reaction.

Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W, Guillet JG, Webster P, Sautes C, Mellman I, Fridman WH. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science. 1992 Jun 26;256(5065):1808-12. doi: 10.1126/science.1535455. PMID: 1535455. Read

Description of the inhibitory motif in FcγR, called “Immunoreceptor Tyrosine Inhibition Motif” (ITIM) responsible for the negative regulation of cell activation.

Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005 Dec 22;353(25):2654-66. doi: 10.1056/NEJMoa051424. PMID: 16371631. Read

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006 Sep 29;313(5795):1960-4. doi: 10.1126/science.1129139. PMID: 17008531. Read

Demonstration that T cells are the major prognosticator of survival in colorectal cancer, allowing to add to the cancer-cancer centric approach, an immune-centric focus.

Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008 Sep 20;26(27):4410-7. doi: 10.1200/JCO.2007.15.0284. PMID: 18802153. Read

Favorable impact of tertiary lymphoid structures (TLS) on the clinical outcome of patients.

Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012 Mar 15;12(4):298-306. doi: 10.1038/nrc3245. PMID: 22419253. Read

The immune contexture concept that forms the framework for identification of biomarkers of survival and therapeutic responses

Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, Jeng YM, Hsiao LP, Lacroix L, Bougoüin A, Moreira M, Lacroix G, Natario I, Adam J, Lucchesi C, Laizet YH, Toulmonde M, Burgess MA, Bolejack V, Reinke D, Wani KM, Wang WL, Lazar AJ, Roland CL, Wargo JA, Italiano A, Sautès-Fridman C, Tawbi HA, Fridman WH. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020 Jan;577(7791):556-560. doi: 10.1038/s41586-019-1906-8. Epub 2020 Jan 15. PMID: 31942077. Read

The demonstration that B cells and Tertiary lymphoid Structures are essential for therapeutic responses to immune check-point inhibition

Vanhersecke L, Brunet M, Guégan JP, Rey C, Bougouin A, Cousin S, Moulec SL, Besse B, Loriot Y, Larroquette M, Soubeyran I, Toulmonde M, Roubaud G, Pernot S, Cabart M, Chomy F, Lefevre C, Bourcier K, Kind M, Giglioli I, Sautès-Fridman C, Velasco V, Courgeon F, Oflazoglu E, Savina A, Marabelle A, Soria JC, Bellera C, Sofeu C, Bessede A, Fridman WH, Loarer FL, Italiano A. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat Cancer. 2021 Aug;2(8):794-802. doi: 10.1038/s43018-021-00232-6. Epub 2021 Aug 12. PMID: 35118423; PMCID: PMC8809887. Read

Predictive impact of TLS on therapeutic responses to immune check-point inhibition is a general phenomenon for many different cancer types  

Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, Giglioli I, Verkarre V, Lacroix G, Verneau J, Sun CM, Laurent-Puig P, Vano YA, Elaïdi R, Méjean A, Sanchez-Salas R, Barret E, Cathelineau X, Oudard S, Reynaud CA, de Reyniès A, Sautès-Fridman C, Fridman WH. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022 Mar 8;55(3):527-541.e5. doi: 10.1016/j.immuni.2022.02.001. Epub 2022 Feb 28. PMID: 35231421.

TLS are sites of generation of antibodies that bind to tumor cells 

Italiano A, Bessede A, Pulido M, Bompas E, Piperno-Neumann S, Chevreau C, Penel N, Bertucci F, Toulmonde M, Bellera C, Guegan JP, Rey C, Sautès-Fridman C, Bougoüin A, Cantarel C, Kind M, Spalato M, Dadone-Montaudie B, Le Loarer F, Blay JY, Fridman WH. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat Med. 2022 Jun;28(6):1199-1206. doi: 10.1038/s41591-022-01821-3. Epub 2022 May 26. PMID: 35618839. Read

First trial showing 40% response to immune check-point inhibition in patients with TLS+ tumors.

Neauport-Sautes C, Bismuth A, Kourilsky FM, Manuel Y. Relationship between HL-A antigens and beta-2-microglobulin as studied by immunofluorescence on the lymphocyte membrane. J Exp Med. 1974 Apr 1;139(4):957-68. doi: 10.1084/jem.139.4.957. PMID: 4131515; PMCID: PMC2139575. Read

Demonstration that MHC-Class I antigens are linked to Beta2-microglobulin on the cell surface

Neauport-Sautes C, Morello D, Freed JH, Nathenson SG, Démant P. The private specificity H-2.4 and the public specificity H-2.28 of the D region are expressed on two independent polypeptide chains. Eur J Immunol. 1977 Aug;7(8):511-5. doi: 10.1002/eji.1830070804. PMID: 71238. Read

Identification of a new locus in the major histocompatibility complex, H-2L

Neauport-Sautes C, Rabourdin-Combe C, Fridman WH. T-cell hybrids bear Fcgamma receptors and secrete suppressor immunoglobulin binding factor. Nature. 1979 Feb 22;277(5698):656-9. doi: 10.1038/277656a0. PMID: 311436. Read

Production of FcγR+ T cell hybrids, identification of soluble forms of FcγR 

Zhang Y, Boesen CC, Radaev S, Brooks AG, Fridman WH, Sautes-Fridman C, Sun PD. Crystal structure of the extracellular domain of a human Fc gamma RIII. Immunity. 2000 Sep;13(3):387-95. doi: 10.1016/s1074-7613(00)00038-8. PMID: 11021536. Read

3D structure of the extracellular domain of FcγR 

Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, Lepelley A, Becht E, Katsahian S, Bizouard G, Validire P, Damotte D, Alifano M, Magdeleinat P, Cremer I, Teillaud JL, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med. 2014 Apr 1;189(7):832-44. doi: 10.1164/rccm.201309-1611OC. PMID: 24484236. Read

Demonstration that B cells located in tertiary lymphoid structures produce anti-tumor IgG antibodies

Giraldo NA, Becht E, Vano Y, Petitprez F, Lacroix L, Validire P, Sanchez-Salas R, Ingels A, Oudard S, Moatti A, Buttard B, Bourass S, Germain C, Cathelineau X, Fridman WH, Sautès-Fridman C. Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma. Clin Cancer Res. 2017 Aug 1;23(15):4416-4428. doi: 10.1158/1078-0432.CCR-16-2848. Epub 2017 Feb 17. PMID: 28213366. Read

Calderaro J, Petitprez F, Becht E, Laurent A, Hirsch TZ, Rousseau B, Luciani A, Amaddeo G, Derman J, Charpy C, Zucman-Rossi J, Fridman WH, Sautès-Fridman C. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 2019 Jan;70(1):58-65. doi: 10.1016/j.jhep.2018.09.003. Epub 2018 Sep 11. PMID: 30213589. Read

Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019 Jun;19(6):307-325. doi: 10.1038/s41568-019-0144-6. PMID: 31092904. Read

Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, Giglioli I, Verkarre V, Lacroix G, Verneau J, Sun CM, Laurent-Puig P, Vano YA, Elaïdi R, Méjean A, Sanchez-Salas R, Barret E, Cathelineau X, Oudard S, Reynaud CA, de Reyniès A, Sautès-Fridman C, Fridman WH. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022 Mar 8;55(3):527-541.e5. doi: 10.1016/j.immuni.2022.02.001. Epub 2022 Feb 28. PMID: 35231421. Read

TLS are sites of generation of plasma cells that migrate in the tumor bed and produce antibodies that bind to tumor cells.

Fridman WH, Meylan M, Pupier G, Calvez A, Hernandez I, Sautès-Fridman C. Tertiary lymphoid structures and B cells: An intratumoral immunity cycle. Immunity. 2023 Oct 10;56(10):2254-2269. doi: 10.1016/j.immuni.2023.08.009. Epub 2023 Sep 11. PMID: 37699391. Read

Tumors are sites of TLS-dependent activation and recall of anti-tumor responses.