Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.

/pdf/prospective-identification-of-tumorigenic-breast-cancer-4c9u5upfc3.pdf

Prospective identification of tumorigenic breast cancer cells

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

Alternative activation of macrophages

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

/pdf/engagement-of-the-pd-1-immunoinhibitory-receptor-by-a-novel-2cb02kpkk5.pdf

Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.

A murine monoclonal antibody (OC125) has been developed that reacts with each of six epithelial ovarian carcinoma cell lines and with cryopreserved tumor tissue from 12 of 20 ovarian cancer patients. By contrast, the antibody does not bind to a variety of nonmalignant tissues, including adult and fetal ovary. OC125 reacts with only 1 of 14 cell lines derived from nonovarian neoplasms and has failed to react with cryostat sections from 12 nonovarian carcinomas.

/pdf/reactivity-of-a-monoclonal-antibody-with-human-ovarian-on0eii33d5.pdf

Reactivity of a monoclonal antibody with human ovarian carcinoma.

https://www.cell.com/imto/pdf/0167-5699(94)90080-9.pdf

The B7 and CD28 receptor families

A human B lymphocyte-specific antigen (B1) was identified and characterized by the use of a monoclonal antibody. By indirect immunofluorescence, cytotoxicity, and quantitative absorption, B1 was present on approximately 9% of the peripheral blood mononuclear cell fraction and >95% of B cells from blood and lymphoid organs in all individuals tested. Monocytes, resting and activated T cells, null cells, and tumors of T cell and myeloid origin were B1 negative. B1 was distinct from standard B cell phenotypic markers, including Ig and Ia antigen. Removal of the B1 positive population in peripheral blood eliminated all B cells capable or responding to pokeweed mitogen by maturation to Ig-producing cells.

Characterization of a human B lymphocyte-specific antigen.

Although presentation of antigen to the T cell receptor is necessary for the initiation of an immune response, additional molecules expressed on antigen-presenting cells deliver essential costimulatory signals. T cell activation, in the absence of costimulation, results in T cell anergy. The B7-1 protein is a costimulator molecule that regulates interleukin-2 (IL-2) secretion by signaling through the pathway that uses CD28 and CTLA-4 (hereafter referred to as the CD28 pathway). We have cloned a counter-receptor of CD28 and CTLA-4, termed B7-2. Although only 26 percent identical to B7-1, B7-2 also costimulates IL-2 production and T cell proliferation. Unlike B7-1, B7-2 messenger RNA is constitutively expressed in unstimulated B cells. It is likely that B7-2 provides a critical early costimulatory signal determining if the T cell will contribute to an immune response or become anergic.

https://science.sciencemag.org/content/sci/262/5135/909.full.pdf

Lee M. Nadler

Papers

Reactivity of a monoclonal antibody with human ovarian carcinoma.

The B7 and CD28 receptor families

Characterization of a human B lymphocyte-specific antigen.

Cloning of B7-2: A CTLA-4 counter-receptor that costimulates human T cell proliferation

Leukocyte typing II