Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to affect response to ICPis in mismatch repair–deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2m in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocom-petent mice, MMRd B2m null cells were tumorigenic and regressed when treated with anti–PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd B2m null tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Human tumors expressing low levels of B2M display increased intra-tumoral CD4+ T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4+ T cells in tumor rejection. Significance: B2M alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers B2M loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4+ T-cell activation.

Cd4 t cell–dependent rejection of beta-2 microglobulin null mismatch repair–deficient tumors

Germano G.;Lu S.;Rospo G.;Stenech D.;Amodio V.;Di Nicolantonio F.;Bardelli A.
2021-01-01

Abstract

Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to affect response to ICPis in mismatch repair–deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2m in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocom-petent mice, MMRd B2m null cells were tumorigenic and regressed when treated with anti–PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd B2m null tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Human tumors expressing low levels of B2M display increased intra-tumoral CD4+ T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4+ T cells in tumor rejection. Significance: B2M alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers B2M loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4+ T-cell activation.
2021
11
7
1844
1859
Germano G.; Lu S.; Rospo G.; Lamba S.; Rousseau B.; Fanelli S.; Stenech D.; Le D.T.; Hays J.; Totaro M.G.; Amodio V.; Chila R.; Mondino A.; Diaz L.A.; Di Nicolantonio F.; Bardelli A.
File in questo prodotto:
File Dimensione Formato  
Germano et al B2M Manuscript 25022021.docx

Accesso riservato

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 179.44 kB
Formato Microsoft Word XML
179.44 kB Microsoft Word XML   Visualizza/Apri   Richiedi una copia
germano amodio 2021.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 6.54 MB
Formato Adobe PDF
6.54 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1794553
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 36
  • ???jsp.display-item.citation.isi??? 35
social impact