Acquired Resistance to Immune Checkpoint Blockade Therapies

Zhao, Xianda; Wangmo, Dechen; Robertson, Matthew J.; Subramanian, Subbaya

doi:10.3390/cancers12051161

Cited by 10 publications

(8 citation statements)

References 85 publications

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“…[5][6][7] However, multiple clinical trials have resulted in disappointing response rates 8 and single-agent efficacy is still low. [9][10][11] Between 10% and 20% of breast cancers are TNBCs. Compared to other breast cancer sub-types, TNBC is more metastatic and has a higher rate of recurrence.…”

Section: Introductionmentioning

confidence: 99%

A novel role for an old target: CD45 for breast cancer immunotherapy

et al. 2021

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Breast cancer subtypes have not shown significant response to current immunomodulatory therapies. Although most subtypes are treatable, triple negative breast cancer (TNBC), an aggressive highly metastatic cancer, comprising 10–20% of breast cancers, remains an unmet medical need. New strategies are needed in order to overcome flaws in the responsiveness to current TNBC therapies. Our aims were: first, to determine the efficacy of a novel immunomodulatory peptide, C24D, on TNBC and second, to elucidate the molecular mechanism by which C24D induces immune-modulating tumor killing. Using mass spectrometry analysis, we identified CD45 as the C24D binding receptor. In vitro and in vivo TNBC models were used to assess the efficacy of C24D in reversing TNBC-induced immunosuppression and in triggering immune-modulated tumor cell killing. The CD45 signal transduction pathway was evaluated by western blot and FACS analyses. We revealed that addition of PBMCs from healthy female donors to TNBC cells results in a cascade of suppressive CD45 intracellular signals. On binding to CD45’s extra-cellular domain on TNBC-suppressed leukocytes, the C24D peptide re-activates the Src family of tyrosine kinases, resulting in specific tumor immune response. In vitro , immune reactivation by C24D results in an increase of CD69+ T and CD69+ NK cells, triggering specific killing of TNBC cells. In vivo , C24D induced CD8+ and activated CD56+ tumor infiltrated cells, resulting in tumor apoptosis. Our results should renew interest in molecules targeting CD45, such as the C24D peptide, as a novel strategy for TNBC immunotherapy.

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Section: Introductionmentioning

confidence: 99%

A novel role for an old target: CD45 for breast cancer immunotherapy

et al. 2021

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“…Alterations in tumor APM can result not only in the downregulation of cell-surface expression MHCI molecules but can also alter the repertoire of antigenic peptides presented to the T lymphocytes. Since successful treatment with ICIs relies on re-activation of T cells, alterations in antigen processing and presentation of antigens can result to impaired antitumor responses and therapy resistance [ 16 , 62 , 63 ].…”

Section: Antigen Processing and Presentation In Cancermentioning

confidence: 99%

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

Mpakali

Stratikos

2021

Cancers

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Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy.

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“…To date, rs671 has not been studied as a potential predictor of ICI treatment, but it may have a complicated, bidirectional, and strong effect on ICI therapy for the following reasons: 1) Cancer cells of ALDH2*2 carriers may show more DNA damage induced by aldehyde exposure during smoking and drinking [ 15 , 16 ], resulting in an increased presentation of antigens to immune cells, which is advantageous in ICI treatment. 2) Because endogenous 4HNE, a typical endogenous aldehyde that accumulates in ALDH2*2 carriers, delays cell proliferation [ 3 , 17 – 20 ], ICI resistance due to genetic mutations in cancer cells [ 21 , 22 ] is less likely to occur. 3) However, high aldehyde concentrations can suppress immune cell activation [ 12 ], making the short-term effect of ICIs difficult to detect.…”

Section: Introductionmentioning

confidence: 99%

ALDH2 polymorphism rs671 is a predictor of PD-1/PD-L1 inhibitor efficacy against thoracic malignancies

et al. 2021

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Background Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation. Methods On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with thoracic malignancies who started ICI therapy in 2016–2019. The cohort consisted of 105 cases, including 64 cases with adenocarcinoma and 30 cases with squamous cell carcinoma, 49 of whom were ALDH2*2 carriers. The first ICI was PD-1/PD-L1 inhibitor (Nivolumab, Pembrolizumab, or Atezolizumab) in all cases. Results The best response to anti-PD-1/PD-L1 therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(−) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5–10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of anti-PD-1/PD-L1 therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(−) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(−) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment sub-group of rs671(+) group (40%). Conclusions Our study suggests that rs671 may be an accurate and cost-effective predictor of PD-1/PD-L1 inhibitor treatment, in which optimal case selection is an important issue.

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Acquired Resistance to Immune Checkpoint Blockade Therapies

Cited by 10 publications

References 85 publications

A novel role for an old target: CD45 for breast cancer immunotherapy

A novel role for an old target: CD45 for breast cancer immunotherapy

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

ALDH2 polymorphism rs671 is a predictor of PD-1/PD-L1 inhibitor efficacy against thoracic malignancies

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