Resistance mechanisms to programmed cell death protein 1 and programmed death ligand 1 inhibitors

Pezeshki, Parmida Sadat; Sharif, Pouya Mahdavi; Rezaei, Nima

doi:10.1080/14712598.2021.1929919

“…(8). However, as mentioned, response to this class of drugs is generally short-lived (8), the anti-drug resistance appears in a relatively short-term period (19), and their side effects are noticeable, and lethal in some instances (20). As a result, it is prudent to meticulously select candidates who bene t most from these agents and to wield the potential of simultaneous blockade of more than one immunomodulator.…”

Section: Discussionmentioning

confidence: 99%

Characterization of immune checkpoints expression and lymphocyte densities of Iranian breast cancer patients; the co-expression status and clinicopathological associates

Pournabee

¹

,

Keshavarz-Fathi

²

,

Esmaeili

³

et al. 2023

Preprint

0

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Background Breast malignancies are now the most common and deadliest type of neoplasms among women worldwide. Novel therapeutic approaches are needed to combat advanced stages of breast cancer. In this study, we aimed to investigate the expression and co-expression status of three immune checkpoints (PD-1, PD-L1, and LAG-3), as well as tumor-infiltrating lymphocytes (TIL) scores, and to further establish their potential correlations with clinicopathologic features. Methods We performed a retrospective study on 361 pathologic samples of breast cancer. Immunohistochemistry was performed to assess the status of the immune checkpoint markers, and H&E staining was used to score TILs. The correlations of the immune checkpoint markers of tumor cells and tumor-associated immune cells and TIL scores with clinicopathological characteristics were analyzed. Results Out of 361 assessed samples, LAG-3 was positive in 51%, while IC PD-L1 and TC PD-L1 were detectable in 36% and 8.9%, respectively. Moreover, both IC PD-L1 and LAG-3 stained positively in 24.4% of samples. IC PD-L1 expression was significantly higher in tumors with higher nuclear, mitotic, and overall grades and tubule formation. In addition, TC PD-L1 and LAG-3 exhibited a similar trend for higher overall grading. Tumors with positive estrogen- and progesterone-receptor (ER and PR) expression had significantly lower IC PD-L1 and TC PD-L1 staining, while LAG-3 positivity was more prevalent in HER2 positive samples. Tumors that were positive for these biomarkers had significantly higher Ki-67 scores. LAG-3 expression showed significant correlations with PD-1 and IC PD-L1 expression. Besides, the co-expression of LAG-3 and IC PD-L1 was significantly more encountered in luminal B and triple-negative subtypes, compared to the luminal A subtype. Regarding TILs, their scoring was significantly higher in ER and PR negative and HER2 positive samples. Intriguingly, samples with positive staining for LAG-3, IC PD-L1, and TC PD-L1 had significantly higher TIL scorings. Conclusions Immune checkpoints show differentially different levels of expression in certain molecular subtypes of breast cancer. Moreover, they reveal a meaningful correlation with each other, proliferation indices, and histologic grades. Finally, a sizable proportion of breast cancers co-express PD-L1 and LAG-3, which will make them appropriate targets for future combined ICIs.

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“…[ 8 ]. However, as mentioned, response to this class of drugs is generally short-lived [ 8 ], the anti-drug resistance appears in a relatively short-term period [ 19 ], and their side effects are noticeable, and lethal in some instances [ 20 ]. As a result, it is prudent to meticulously select candidates who benefit most from these agents and to wield the potential of simultaneous blockade of more than one immunomodulator.…”

Section: Discussionmentioning

confidence: 99%

Characterization of immune checkpoints expression and lymphocyte densities of iranian breast cancer patients; the co-expression status and clinicopathological associates

Pournabee

¹

,

Keshavarz-Fathi

²

,

Esmaeili

³

et al. 2023

BMC Cancer

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Background Breast malignancies are now the most common and deadliest type of neoplasms among women worldwide. Novel therapeutic approaches are needed to combat advanced stages of breast cancer. In this study, we aimed to investigate the expression and co-expression status of three immune checkpoints (PD-1, PD-L1, and LAG-3), as well as tumor-infiltrating lymphocytes (TIL) scores, and to further establish their potential correlations with clinicopathologic features. Methods We performed a retrospective study on 361 pathologic samples of breast cancer. Immunohistochemistry was performed to assess the status of the immune checkpoint markers, and H&E staining was used to score TILs. The correlations of the immune checkpoint markers of tumor cells and tumor-associated immune cells and TIL scores with clinicopathological characteristics were analyzed. Results Out of 361 assessed samples, LAG-3 was positive in 51%, while IC PD-L1 and TC PD-L1 were detectable in 36% and 8.9%, respectively. Moreover, both IC PD-L1 and LAG-3 stained positively in 24.4% of samples. IC PD-L1 expression was significantly higher in tumors with higher nuclear, mitotic, and overall grades and tubule formation. In addition, TC PD-L1 and LAG-3 exhibited a similar trend for higher overall grading. Tumors with positive estrogen- and progesterone-receptor (ER and PR) expression had significantly lower IC PD-L1 and TC PD-L1 staining, while LAG-3 positivity was more prevalent in HER2 positive samples. Tumors that were positive for these biomarkers had significantly higher Ki-67 scores. LAG-3 expression showed significant correlations with PD-1 and IC PD-L1 expression. Besides, the co-expression of LAG-3 and IC PD-L1 was significantly more encountered in luminal B and triple-negative subtypes, compared to the luminal A subtype. Regarding TILs, their scoring was significantly higher in ER and PR negative and HER2 positive samples. Intriguingly, samples with positive staining for LAG-3, IC PD-L1, and TC PD-L1 had significantly higher TIL scorings. Conclusions Immune checkpoints show differentially different levels of expression in certain molecular subtypes of breast cancer. Moreover, they reveal a meaningful correlation with each other, proliferation indices, and histologic grades. Finally, a sizable proportion of breast cancers co-express PD-L1 and LAG-3, which will make them appropriate targets for future combined ICIs.

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“…The mAbs are usually tailored to prohibit virus entry through disrupting the interaction between host cells, the ACE2 receptor, and the S protein. However, the administration of ICIs is a viable alternative as there is a high complexity in immune cell count, regulatory protein expression, and cytokine secretion [64]. A randomised control clinical trial is currently assessing the efficiency of the anti-PD1 agent and thymosin on COVID-19 patients suffering with lymphopenia and severe respiratory failure.…”

Section: Immune Checkpoint Inhibitors Against Covid-19mentioning

confidence: 99%

“…Phase II of this trial goes on to evaluate the consequences of anti-NKG2A (monalizumab), anti-C5aR (avadoralimab) and autophagy inhibitor GNS561 administration to COVID-19 patients with either advanced or metastatic cancer. This trial consists of four arms, divided into two cohorts of patients: one consists of patients with mild and asymptomatic symptoms; another consists of patients suffering from moderate or severe symptoms [64]. NKG2A and C5aR are ICIs that reside in a more unique class.…”

Section: Immune Checkpoint Inhibitors Against Covid-19mentioning

confidence: 99%

Cellular Immunotherapy and the Lung

Daly

¹

,

O’Sullivan

²

,

MacLoughlin

³

2021

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The new era of cellular immunotherapies has provided state-of-the-art and efficient strategies for the prevention and treatment of cancer and infectious diseases. Cellular immunotherapies are at the forefront of innovative medical care, including adoptive T cell therapies, cancer vaccines, NK cell therapies, and immune checkpoint inhibitors. The focus of this review is on cellular immunotherapies and their application in the lung, as respiratory diseases remain one of the main causes of death worldwide. The ongoing global pandemic has shed a new light on respiratory viruses, with a key area of concern being how to combat and control their infections. The focus of cellular immunotherapies has largely been on treating cancer and has had major successes in the past few years. However, recent preclinical and clinical studies using these immunotherapies for respiratory viral infections demonstrate promising potential. Therefore, in this review we explore the use of multiple cellular immunotherapies in treating viral respiratory infections, along with investigating several routes of administration with an emphasis on inhaled immunotherapies.

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Resistance mechanisms to programmed cell death protein 1 and programmed death ligand 1 inhibitors

Cited by 7 publications

References 153 publications

Characterization of immune checkpoints expression and lymphocyte densities of Iranian breast cancer patients; the co-expression status and clinicopathological associates

Characterization of immune checkpoints expression and lymphocyte densities of Iranian breast cancer patients; the co-expression status and clinicopathological associates

Characterization of immune checkpoints expression and lymphocyte densities of iranian breast cancer patients; the co-expression status and clinicopathological associates

Cellular Immunotherapy and the Lung

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