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

Mpakali, Anastasia; Stratikos, Efstratios

doi:10.3390/cancers13010134

Cited by 83 publications

(79 citation statements)

References 282 publications

(205 reference statements)

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“…Striking advances have been made in anticancer immunotherapy in the last decade due to the use of monoclonal antibodies referred to as ICBs [ 8 , 9 ], able to foster pre-existing immunity against both TAAs and neo-antigens. These successes definitely proved that cancer can be treated and cured by manipulating the immune system.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Antitumor CD8+ T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles

Ferrantelli

Manfredi

Chiozzini

et al. 2021

Cancers

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We developed an innovative method to induce antigen-specific CD8+ T cytotoxic lymphocyte (CTL) immunity based on in vivo engineering of extracellular vesicles (EVs). This approach employs a DNA vector expressing a mutated HIV-1 Nef protein (Nefmut) deprived of the anti-cellular effects typical of the wild-type isoform, meanwhile showing an unusual efficiency of incorporation into EVs. This function persists even when foreign antigens are fused to its C-terminus. In this way, Nefmut traffics large amounts of antigens fused to it into EVs spontaneously released by the recipient cells. We previously provided evidence that mice injected with a DNA vector expressing the Nefmut/HPV16-E7 fusion protein developed an E7-specific CTL immune response as detected 2 weeks after the second immunization. Here, we extended and optimized the anti-HPV16 CD8+ T cell immune response induced by the endogenously engineered EVs, and evaluated the therapeutic antitumor efficacy over time. We found that the co-injection of DNA vectors expressing Nefmut fused with E6 and E7 generated a stronger anti-HPV16 immune response compared to that observed in mice injected with the single vectors. When HPV16-E6 and -E7 co-expressing tumor cells were implanted before immunization, all mice survived at day 44, whereas no mice injected with either void or Nefmut-expressing vectors survived until day 32 after tumor implantation. A substantial part of immunized mice (7 out of 12) cleared the tumor. When the cured mice were re-challenged with a second tumor cell implantation, none of them developed tumors. Both E6- and E7-specific CD8+ T immunities were still detectable at the end of the observation time. We concluded that the immunity elicited by engineered EVs, besides counteracting and curing already developed tumors, was strong enough to guarantee the resistance to additional tumor attacks. These results can be of relevance for the therapy of both metastatic and relapsing tumors.

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Section: Introductionmentioning

confidence: 99%

Long-Term Antitumor CD8+ T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles

Ferrantelli

Manfredi

Chiozzini

et al. 2021

Cancers

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“…ERAP1 is polymorphic and several common allotypes exist in the population affecting its functional properties and predisposition to disease such as cancer and autoimmunity 4 , 5 . Due to its important role in adaptive immune responses, ERAP1 is an emerging target for cancer immunotherapy and inflammatory diseases with autoimmune etiology 6 – 8 .…”

Section: Introductionmentioning

confidence: 99%

The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I

Mavridis

Mpakali

Zoidakis

et al. 2021

Sci Rep

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Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.

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“…Besides these, epigenetic dysregulation, post-translational modifications, post-transcriptional modifications, and oncogene activation can cause reversible alterations in MHC I pathway [37]. Mutations in MHC class I heavy chain and β2 subunits especially can irreversibly affect tumor-specific antigen presentation and influence CPI resistance [38,39]. There have been investigations to find an association between HLA loss, MHC class I impairment, and reduced response to CPI immunotherapy [40].…”

Section: The Immunosuppressive Landscape Of Hnsccmentioning

confidence: 99%

“…There have been investigations to find an association between HLA loss, MHC class I impairment, and reduced response to CPI immunotherapy [40]. Tumor cell mutations [interferon (IFN) γ pathway alterations, phosphatase and tensin homolog (PTEN) mutations, β2 mutation] may not allow immunotherapy to work leading to primary or acquired resistance [39,41]. NK or γδ T cell-based adoptive cell transfer (ACT; MHC unrestricted) and HLA upregulation by cytokines may be a therapeutic strategy to overcome these obstacles.…”

Section: The Immunosuppressive Landscape Of Hnsccmentioning

confidence: 99%

Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC) is a relatively widespread cancer with high mortality rates. Many patients with locally advanced disease are treated with combinations of surgery, radiation, and chemotherapy, while others are considered incurable and develop recurrent/metastatic(R/M) disease. Despite these treatment modalities, the 5-year survival rate of HNSCC has remained at 50% due to limited treatment options in patients with recurrent disease. Immunotherapy has been shown to induce durable responses in R/M patients, but only a minority of patients currently respond. A major hurdle in tumor immunotherapy is identifying the non-responders and markers to predict resistance in patients who at first responded to the therapy. In HNSCC patients, the tumor microenvironment (TME) assumes a vital role to either diminish or augment immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. In this review, the impact of TME on the efficiency of immunotherapy, addressing the factors that mediate therapy resistance are highlighted. The composition of the TME encompassing the immunosuppressive cells including myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), mesenchymal stem cell (MSC), cancer-associated fibroblast (CAF), and tumor-associated macrophages (TAMs) and intrinsic factors like hypoxia, reactive oxygen species (ROS),extracellular matrix (ECM), angiogenesis, and epithelial-mesenchymal transition (EMT), how this debilitates immunosurveillance, and also discuss existing and potential strategies aimed at targeting these cellular and molecular TME components are reviewed. Understanding the interactions between the TME and immunotherapy is not only important in dissevering the mechanisms of action of immunosuppression but also offers scope for developing newer strategies to improve the competence of current immunotherapies.

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

Cited by 83 publications

References 282 publications

Long-Term Antitumor CD8+ T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles

Long-Term Antitumor CD8+ T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles

The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I

Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy

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