Immune Checkpoint Therapy For Cancer Research Articles

Inhibition of APOE potentiates immune checkpoint therapy for cancer.

Checkpoint immunotherapy is capable of unleashing T cells for controlling tumor, whereas it is destroyed by immunosuppressive myeloid cell. Apoprotein E (APOE) refers to a ligand in terms of the members of low-density lipoprotein (LDL) receptor family for mediating Apoprotein B-involving atherogenic lipoprotein clearance. Besides, tumor-infiltration macrophage can express APOE. The present study reported Apoe-/- mice to exhibit higher resistance toward the development of three types of carcinomas as compared with mice with wild type and to have greater responses to αPD-1 (anti-PD-1) immunotherapy. Moreover, treatment by exploiting APOE inhibitor (COG 133TFA, αAPOE) was capable of curbing tumor development and fostering regression if in combination of αPD-1. According to single-cell RNA sequencing (scRNA-seq), Apoe deletion was correlated with the decline of C1QC+ and CCR2+ macrophage within tumor infiltration, and mass spectrometry results noticeably showed down-regulated the number of M2 macrophages as well. Furthermore, APOE expression in cancer patients resistant to αPD-1 treatment significantly exceeded that in the sensitive group. For this reason, APOE is likely to be targeted for modifying tumor macrophage infiltrate and augmenting checkpoint immunotherapy.

Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.

Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors.

Autophosphorylation and the Dynamics of the Activation of Lck

Lck (lymphocyte-specific protein tyrosine kinase) is an enzyme which plays a number of important roles in the function of immune cells. It belongs to the Src family of kinases which are known to undergo autophosphorylation. It turns out that this leads to a remarkable variety of dynamical behaviour which can occur during their activation. We prove that in the presence of autophosphorylation one phenomenon, bistability, already occurs in a mathematical model for a protein with a single phosphorylation site. We further show that a certain model of Lck exhibits oscillations. Finally, we discuss the relations of these results to models in the literature which involve Lck and describe specific biological processes, such as the early stages of T cell activation and the stimulation of T cell responses resulting from the suppression of PD-1 signalling which is important in immune checkpoint therapy for cancer.

Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.

Despite its great success, cancer immune therapy is still of limited efficacy in the majority of cancer patients1,2. Many efforts are underway to identify novel approaches to enhance immune checkpoint therapy3–5. Here we show that inhibition of PCSK9, a key protein in regulating cholesterol metabolism6–8, can boost tumor response to immune checkpoint therapy, albeit through a mechanism independent of its cholesterol regulating functions. Deletion of the PCSK9 gene in murine cancer cells significantly attenuated or prevented their growth in mice in a cytotoxic T-cell-dependent manner. It also enhanced the efficacy of anti-PD1 immune checkpoint therapy significantly. Furthermore, clinically approved PCSK9-neutralizing antibodies could synergize with anti-PD1 therapy in suppressing tumor growth in murine tumor models. PCSK9 inhibition, either through genetic deletion or PCSK9 antibodies, caused a significant increase in tumor cell surface major histocompatibility protein class I (MHC I) expression, which promoted robust intratumoral infiltration of cytotoxic T-cells. Mechanistically, we discovered that PCSK9 could disrupt the recycling of MHC I to the cell surface by promoting its relocation and degradation in the lysosome through physical association. Taken together, we believe PCSK9 inhibition is a promising strategy to enhance cancer immune checkpoint therapy.

Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α.

Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.

Dissecting the mechanisms of immune checkpoint therapy.

Immune checkpoint therapy with antibodies targeting CTLA4 or PD1/PDL1 has led to durable regression of disease and cures for a subset of patients with cancer, which has led to increased efforts to develop combination immunotherapy strategies to benefit an even greater number of patients. However, questions remain as to which combinations should be used and in which population of patients. In 2019, several studies reported on the differential impact of targeting CTLA4 and/or PD1 on T cell responses, with clear evidence that both CD4+ and CD8+ T cell responses are needed. These data highlight the complementary nature of targeting CTLA4 and PD1 to drive both CD4+ and CD8+ effector T cell responses, which should be considered in future treatment strategies. Furthermore, reverse translational studies, which provide immune response data from patients receiving immune checkpoint therapy, have revealed resistance mechanisms that indicate relevant targets for combination strategies. Taken together, future treatments will likely consist of anti-CTLA4 plus anti-PD1 with addition of individualized therapy on the basis of tumour type and site of metastatic disease. Studies of immune checkpoint therapy for cancer in 2019 uncovered critical insights into the differences between targeting CTLA4 versus PD1 and the role of particular T cell subsets in immune responses to cancer. Moreover, reverse translational studies are informing our understanding of resistance and response mechanisms in patients.

Development of immune checkpoint therapy for cancer.

Since the early 20th century, immunologists have investigated mechanisms that protect vertebrates from damaging immune responses against self-antigens by mature lymphocytes, i.e., peripheral tolerance. These mechanisms have been increasingly delineated at the molecular level, ultimately culminating in new therapeutics that have revolutionized clinical oncology. Here, we describe basic science and clinical discoveries that converge mainly on two molecules, CTLA-4 and PD-1, that were recognized with the 2018 Nobel Prize in Physiology or Medicine awarded to James Allison and Tasuku Honjo. We discuss their investigations and those of many others in the field that contravene tolerance through checkpoint inhibition to boost immune killing of malignant cells. We also discuss the mechanisms underlying each therapy, the efficacy achieved, and the complications of therapy. Finally, we hint at research questions for the future that could widen the success of cancer immunotherapy.

MON-608 Incidence And Onset Of Thyroid Dysfunction In Patients Treated With Pd-1 Inhibitors At A Medical Center

Background: The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Pembrolizumab and Nivolumab are anti-PD-1 monoclonal antibodies. Thyroid dysfunction is a known adverse effect of these drugs, but there is limited data on incidence.1,2 Our aim was to determine the incidence in a consecutive series of patients treated with these drugs. Methods: The study design was a case series. Data from all the patients who received Nivolumab or Pembrolizumab at our Medical Center from July 2016 to July 2018 were reviewed. 123 patients were identified; 21 patients were excluded due to abnormal baseline thyroid function or missing data. 102 patients were included in the study. In addition to descriptive statistics (univariate), bivariate analysis was conducted using the t-test, chi-square, and fisher exact test. Results: The population was male (100%), predominantly white (80%) and elderly (mean age 68.2 + 6.9 years). Indication for treatment was non-small cell lung cancer (NSCLC) in 66.7%. Among the 102 patients, 13 were found to have abnormal thyroid function after medication exposure. 10 of whom developed overt hypothyroidism. Two out of the 10 patients, initially developed thyroiditis, which later progressed to overt hypothyroidism. Three patients developed hyperthyroidism. Onset of thyroid dysfunction was noted within 3.5 doses (range 1-9) and first 7 weeks (range 2-16 weeks) of medication exposure. There were no significant differences between groups regarding age (66.1 vs 68.4 years), race (85 vs 95% white), type of cancer (61.5 vs 68.5% NSCLC), type of drug used (80.9 vs 76.9% Nivolumab) or total number of immunotherapy doses (15.4 vs 10.3) in whom thyroid dysfunction did and did not occur, respectively (all p > 0.2). Discussion: Anti-PD-1 monoclonal antibody-induced thyroid dysfunction is common (12.7%). Yet, there are no standardized protocols of the frequency of thyroid function monitoring in patients treated with these drugs. Interestingly, the onset of thyroid dysfunction occurred on an average within first 7 weeks and 3-4 doses of treatment initiation. Most patients who developed hypothyroidism required long term supplementation. There is no clear association between the number of doses and abnormal thyroid function as previously reported.1 We suggest that patients that will be started on anti-PD-1 monoclonal antibodies should get thyroid function testing at baseline and monthly for at least the first 2-4 months of treatment, since later the incidence of thyroid abnormalities decreases significantly.

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab

The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 μU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.

Great science inspires us to tackle the issue of data reproducibility

This special MBoC edition celebrates the American Society for Cell Biology’s 2015 award winners by featuring essays describing their inspiring scientific journeys and sharing their impressive wisdom. These articles remind us that, while much attention has recently been focused on concerns about research practices and data reproducibility, we live in an era of unprecedented achievements in biomedical research discovery, such as immune checkpoint therapy for cancer, which arose directly out of basic research (Sharma and Allison, 2015 ). David G. Drubin Editor-in-Chief As the successful careers of these ASCB awardees serve to remind us, it is important that all scientists promote research practices and standards that result in high-quality, reproducible research. If the scientific community cannot convince the public that we have control of this issue, we risk reduced funding and imposition of guidelines developed and enforced by government legislators. Because peer-reviewed publications are both the product of research and the vehicles for communicating scientific discoveries, journals have a critical role to play, promoting the practices that make research reproducible. It is appropriate that scientist-run journals like MBoC take a lead in this effort. MBoC has always embraced a “back-to-basics” approach to promote research integrity. In other words, major innovations are not needed to promote reproducibility, just an emphasis on sound fundamentals. Reproducibility must begin with those individuals performing the initial study. First and foremost, it is vital that investigators perform adequate independent replicates and report: 1) how many independent replicates were performed and 2) the variance in the results. Appropriate statistical practices are important but are not a panacea. This is because there is a difference between precision and accuracy. An experimental setup with a systematic design flaw can produce data that are precise but inaccurate. Second, it is vital that the variables in each procedure be altered systematically to determine which parameters are critical for making results reproducible. Having done these two things, it is next essential that the study be communicated in sufficient detail to allow others to reproduce the key findings. Finally, one of the best ways to insure that a result is correct is to get the same answer using at least two independent approaches. In their classic study, Jamieson and Palade (1967) used both cell fractionation and radioautography to discover the intracellular trafficking route. Journals are part of this reproducibility issue in another way. Many scientists feel that it is necessary to publish in high-profile journals to secure funding, employment, and career advancement. Attempting to publish in such journals, however, may make authors feel the need to oversimplify their results and omit inconvenient data, both of which compromise the integrity of the reported results. Moreover, higher-profile journals tend to have severe constraints on article length, compounding these problems. Vital to making research reproducible is being able to report ALL of the nuances of the experimental procedures and results, including “inconvenient facts” that might not fit perfectly with the major findings of a study. One back-to-basics solution to this problem is to publish research articles in professional society journals like MBoC that are concerned only with results being new and true and not with their pop­ular appeal or flashiness. MBoC and some other professional society journals do not have artificial limits on the number of figures or the length of the text. Such limits impair the ability to provide sufficient detail so others can reproduce published work. A promising way to address reproducibility issues is through development of field-specific, community standards. Achieving reproducibility can be challenging, because scientific research is difficult and protocols are often complex (Aschwanden and King, 2015 ). However, this is not an excuse for publication of results that cannot be reproduced. Rather, it is an important acknowledgment of the reality that there are a lot of variables in performing experiments and in collecting and analyzing data. Seemingly insignificant changes in execution or analysis can have profound impacts on results. Because the ways in which complex phenomena are observed, classified, and reported are often research area specific, one-size-fits-all solutions for the reproducibility issue are unattainable. The autophagy field has developed its own standards by consensus (Klionsky et al., 2012 ), providing a powerful example for others to follow. Many of these approaches to the data-reproducibility problem are discussed in a report by the ASCB Data Reproducibility Task Force (American Society for Cell Biology, 2015 ). In the near future, MBoC will be developing strategies to implement the task force’s recommendations in ways that do not place excessive administrative burdens on authors. In closing, I offer congratulations to the 2015 ASCB award winners! You inspire us all with your creativity and passion, exemplify sound science practices, and remind us that great scientific achievements result when all of these elements are combined.

CD47 blockade as another immune checkpoint therapy for cancer.

The role of CD47—often expressed on tumor cells—as a 'don't eat me' signal that inhibits macrophage phagocytosis is well established. But new work reveals a major role for other immune cell types—T cells and dendritic cells—in the anti-tumor effects of therapeutic CD47 blockade.