Publisher Summary It is known for some time that malignant transformation of human cells may be associated with the appearance of tumor associated antigens (TAA). Decades of research have been aimed at the identification of TAA that can serve as targets for the immunotherapy of malignant diseases. The dramatic progress in the understanding of molecular basis of target cell recognition by cytotoxic T lymphocytes (CTL) has provided the background to design effective strategies to identify TAA recognized by CTL on tumor cells. The extensive application of these strategies by a number of investigators has resulted in the identification of various families of TAA on various types of solid tumors. Mouse tumor models have played an important role in elucidating the mechanisms by which the immune system interacts with tumor cells and eradicates cancer. The second line of evidence is represented by the phenomenon of a “mixed response.” A mixed response occurs rather frequently in patients with metastases, although its actual frequency is not documented. Mixed responses are characterized by the different behavior of synchronous metastases in response to T cell-based immunotherapy. This important finding suggests that TAA-specific CTL may be present in some cancer patients but are unable to attack tumor cells due to the presence of inhibitory receptors.

Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance.

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

/pdf/cancer-immune-evasion-through-loss-of-mhc-class-i-antigen-25ts7p6mf1.pdf

Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation.

https://www.cell.com/trends/immunology/pdf/0167-5699(93)90264-L.pdf

Natural history of HLA expression during tumour development

Publisher Summary The chapter presents that the primary and metastatic tumor cell growth results from the development of sophisticated molecular and biological mechanisms that allow tumor cells to escape immune surveillance. These escape mechanisms are selected by the cancer cells after a period of interaction with the immune system. Among these mechanisms, the MHC class I phenotypic alteration that occurs in tumor cells plays a leading role in the tumor–host scenario since these are crucial molecules for antigen presentation to T cells and modulation of NK activity. This chapter discusses the major HLA class I phenotypic alterations found in human tumors, with special attention paid to the molecular mechanisms responsible for their generation. The chapter also describes the HLA class I alterations that are detected in tumors derived from different tissues of the body, such as the bladder, breast, colon and rectum, larynx, lung, kidney, melanocytes, pancreas, and prostate. The issue of nonclassical HLA class I molecule expression in tumor cell lines and tumor tissues and its possible role in immune escape is also discussed, as are the implications of these findings for T cell-based immunotherapy. The chapter concludes with the experimental data supporting the hypothesis that the MHC class I-negative tumor variants are selected in vivo by cytotoxic lymphocyte (CTL) responses against MHC class I-positive tumor cells.

MHC antigens and tumor escape from immune surveillance.

Acquisition of human papillomavirus (HPV) results in an infection of variable duration which may or may not be associated with clinically apparent lesions. Lesions caused by skintropic HPV types generally manifest as cutaneous warts and most often resolve over a period of months to years. On the other hand, anogenital infections are more likely to remain clinically inapparent. The development of DNA amplificationbased tests has demonstrated that anogenital infections are quite common and generally self-limited. For example, we and others have shown by PCR testing of multiple samples collected at different points in time-that 70 to 90% of sexually active adolescents and young women who develop an incident cervical HPV infection will show clearance of infection within 12 to 30 months (47, 61, 94). The factors influencing the natural history of these infections are not well understood. Given that persistent anogenital infection with oncogenic HPV types is associated with increased risk of neoplasia and invasive cancers (22, 59, 70, 71, 94, 124) and that cervical carcinoma remains a leading cause of death among women in developing countries (129), understanding these factors is of considerable importance. Substantial effort has been directed recently at understanding the role of the host’s immune response in the natural history of HPV, and in particular, anti-viral, cell-mediated immunity. Empirical evidence for the importance of cell-mediated immunity in control of HPV infection comes from an extensive body of literature documenting the increased prevalence of HPV infection and associated disease among immunosuppressed populations, including those with iatrogenic immunosuppression such as renal transplant recipients and individuals with human immunodeficiency virus (HIV) infection. Sillman and coauthors (128) reported in 1984 on 20 immunosuppressed women with various causes of immunosuppression who had lower genital neoplasia, describing evidence of associated HPV infection in all 20. Penn, in 1986, reported a 100-fold increase in cancer of the vulva and anus in renal transplant recipients (111). In the 1990s, as molecular testing for HPV infection came into its own, several reports confirmed increased incidence of HPV infection (50) and associated morbidities, including warts (77) and cervical squamous intraepithelial lesions (SIL) (104), among immunosuppressed renal

https://cvi.asm.org/content/cdli/8/2/209.full.pdf

Cell-mediated immune response to human papillomavirus infection.

The expression of MHC class-I antigens was analysed in 67 cervical carcinoma biopsies; 16% of the biopsies showed complete or heterogeneous loss of HLA expression as judged by reactivity with antibodies recognizing monomorphic determinants of the class-I heavy chain bound to beta 2 microglobulin (beta 2m). In addition, other biopsies showed a loss in expression of particular allelic products: 23% for HLA-A2; 17% for HLA-A3; 23% for HLA-Bw4 and 19% for HLA-Bw6. Three biopsies showed changes at 2 alleles, 2 of which were at both HLA-A and -B loci. Down-regulation of class-I expression may be virally mediated and HPV DNA is frequently found in cervical carcinomas. However, there appeared to be no direct correlation between the detection of HPV 16 or 18 DNA in these tumours and changes in HLA expression. There was also no correlation with the expression of the oncofoetal antigen 5T4. Our results show that a significant proportion (at least 30%) of the cervical carcinomas showed some alteration in MHC class-I expression. Such changes may allow tumours to evade immune surveillance with more rapid progression. There was, however, no correlation with tumour type, degree of differentiation or stage of disease at presentation.

Loss of MHC class‐I expression in cervical carcinomas

Sera from patients with cervical cancer, cervical intraepithelial neoplasia (CIN) and non-genital cancers, and from healthy individuals, were investigated for antibodies to human papilloma virus (HPV) early proteins E4, E6 and E7 and the major capsid protein LI by Western blot analysis of recombinant HPV proteins. There was a significantly higher prevalence of sera with antibodies to E6 in cervical cancer patients than in healthy individuals or in CIN or non-genital-cancer patients. Antibodies to E7 were detected in 25% of cervical-cancer patients, which is significantly higher than in HPV-associated cervical lesions or in control populations, but not significantly different from the incidence in patients with non-genital cancers. Antibodies to LI were found more frequently in CIN, while antibodies to E4 had a similar prevalence in cervical-cancer, cervical-dysplasia and non-genital-cancer groups, with 24% in the controls. The inability to detect antibodies to E6 and E7 in the majority of cervical-cancer patients limits the application of this methodology to the monitoring of HPV infection and the development of cervical cancer. However, the latter approach may be useful in combination with other assay systems which allow detection of different, including conformational, epitopes of HPV E6 and/or E7 recombinant proteins.

Serological response to HPV 16 in cervical dysplasia and neoplasia: correlation of antibodies to E6 with cervical cancer.

HLA expression in pre-invasive cervical neoplasia in relation to human papilloma virus infection

A number of diverse biologic parameters have been assessed prior to treatment in a series of patients with cervical carcinoma. Factors analyzed were HPV DNA presence, MHC class I expression, expression of the oncofetal antigen 5T4, the proportions of macrophages, lymphocytes and granulocytes in cell suspensions prepared from tumors, in vitro colony-forming efficiency (CFE) and a measure of intrinsic radiosensitivity, surviving fraction at 2 Gy. Several associations were found. First, HPV DNA-negative tumors contained a small, but significant, decreased number of tumor infiltrating macrophages compared with HPV DNA-positive tumors. Secondly, patients with HPV-positive tumors were significantly younger than those where no HPV was detected. Thirdly, loss of one or more specific alleles in MHC class I positive tumors resulted in higher numbers of tumor lymphocytes and CFEs. Finally, strong expression of the 5T4 antigen was related to a reduction in the proportion of macrophages in tumor cell suspensions. In addition, for stage I and II patients expression of the MHC class I molecule was associated with improved survival compared with patients with tumors where loss of expression was seen.

Evaluation of multiple biologic parameters in cervical carcinoma: high macrophage infiltration in HPV-associated tumors.

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Loss of MHC class‐I expression in cervical carcinomas

Serological response to HPV 16 in cervical dysplasia and neoplasia: correlation of antibodies to E6 with cervical cancer.

HLA expression in pre-invasive cervical neoplasia in relation to human papilloma virus infection

Evaluation of multiple biologic parameters in cervical carcinoma: high macrophage infiltration in HPV-associated tumors.