Reference Detail

Ref Type

Journal Article

PMID

(29070816)

Authors

Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, Bjorgaard SL, Hammond MR, Vitzthum H, Blackmon SM, Frederick DT, Hazar-Rethinam M, Nadres BA, Van Seventer EE, Shukla SA, Yizhak K, Ray JP, Rosebrock D, Livitz D, Adalsteinsson V, Getz G, Duncan LM, Li B, Corcoran RB, Lawrence DP, Stemmer-Rachamimov A, Boland GM, Landau DA, Flaherty KT, Sullivan RJ, Hacohen N

Title

Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	8	1	2017 10 26	1136	Nat Commun

URL

Abstract Text

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
B2M	D96G	missense	unknown	B2M D96G lies within the Ig-like C1-type domain of the B2m protein (UniProt.org). D96G has been identified in the scientific literature (PMID: 29070816), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	G63fs	frameshift	unknown	B2M G63fs results in a change in the amino acid sequence of the B2m protein beginning at 63 of 119, likely resulting in premature truncation of the functional protein (UniProt.org). G63fs has been identified in the scientific literature (PMID: 29070816), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	L13fs	frameshift	loss of function - predicted	B2M L13fs results in a change in the amino acid sequence of the B2m protein beginning at aa 13 of 119, likely resulting in premature truncation of the functional protein (UniProt.org). L13fs is predicted to confer a loss of function to the B2m protein as indicated by lack of MHC class I membrane localization (PMID: 29070816).
B2M	S14fs	frameshift	loss of function	B2M S14fs results in a change in the amino acid sequence of the B2m protein beginning at aa 14 of 119, likely resulting in premature truncation of the functional protein (UniProt.org). S14fs confers a loss of function to the B2m protein as demonstrated by lack of MHC class I membrane localization (PMID: 27433843, PMID: 29070816).	Y
B2M	V29fs	frameshift	unknown	B2M V29fs results in a change in the amino acid sequence of the B2m protein beginning at 29 of 119, likely resulting in premature truncation of the functional protein (UniProt.org). V29fs has been identified in the scientific literature (PMID: 29070816), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
MSH2	P476S	missense	unknown	MSH2 P476S lies within the clamp domain of the Msh2 protein (PMID: 17531815). P476S has been identified in the scientific literature (PMID: 29070816), but has not been biochemically characterized and therefore, its effect on Msh2 protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
B2M L13fs B2M LOH	melanoma	predicted - resistant	Ipilimumab	Case Reports/Case Series	Actionable	In a clinical case study, B2M loss of heterozygosity (LOH) and L13fs were identified as acquired mutations in one lineage of resistant tumor cells in a melanoma patient whose disease progressed on Yervoy (ipilimumab) treatment, B2M LOH and L13fs were also identified in the pre-treatment biopsy of a melanoma patient who did not respond to Yervoy (ipilimumab) treatment (PMID: 29070816).	29070816
B2M V29fs B2M LOH	melanoma	predicted - resistant	Ipilimumab	Case Reports/Case Series	Actionable	In a retrospective analysis, B2M loss of heterozygosity (LOH) and V29fs were identified in the pre-treatment biopsy of a patient with melanoma who did not respond to Yervoy (ipilimumab) treatment (PMID: 29070816).	29070816
B2M negative	melanoma	predicted - resistant	Nivolumab	Case Reports/Case Series	Actionable	In a clinical case study, loss of B2m protein expression was identified during and after disease progression in a melanoma patient harboring B2M loss of heterozygosity (LOH), whose disease briefly responded to Opdivo (nivolumab) treatment (PMID: 29070816).	29070816
B2M LOH	melanoma	predicted - resistant	Ipilimumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, B2M loss of heterozygosity (LOH) was significantly enriched in pre-treatment biopsies of melanoma patients who did not respond to Yervoy (ipilimumab) compared to those who responded (20/69, 28.9% vs 4/36, 11.1%, p=0.01), and was associated with poorer overall survival (p=0.01) (PMID: 29070816).	29070816
B2M S14fs B2M G63fs	melanoma	predicted - resistant	Ipilimumab	Case Reports/Case Series	Actionable	In a clinical case study, B2M S14fs and G63fs were identified as acquired mutations in a melanoma patient whose disease progressed on Yervoy (ipilimumab) treatment (PMID: 29070816).	29070816
B2M S14fs B2M LOH	melanoma	predicted - resistant	Ipilimumab	Case Reports/Case Series	Actionable	In a clinical case study, B2M loss of heterozygosity (LOH) and S14fs were identified as acquired mutations in one lineage of resistant tumor cells in a melanoma patient whose disease progressed on Yervoy (ipilimumab) treatment (PMID: 29070816).	29070816
B2M L13fs B2M LOH	melanoma	predicted - resistant	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical case study, a melanoma patient with acquired B2M loss of heterozygosity (LOH) and L13fs did not respond to Keytruda (pembrolizumab) treatment (PMID: 29070816).	29070816
B2M LOH	melanoma	predicted - resistant	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, the presence of B2M loss of heterozygosity (LOH) in the pre-treatment biopsies was significantly associated with worse overall survival (p=0.006) in melanoma patients treated with Keytruda (pembrolizumab) (PMID: 29070816).	29070816
B2M D96G B2M LOH	melanoma	predicted - resistant	Ipilimumab	Case Reports/Case Series	Actionable	In a retrospective analysis, B2M loss of heterozygosity (LOH) and D96G were identified in the pre-treatment biopsy of a patient with melanoma who did not respond to Yervoy (ipilimumab) treatment (PMID: 29070816).	29070816