Cancer Immunobiology and Immunotherapy

Cancer involves a loss of the ability of cells to control their cell cycle, the stages each eukaryotic cell goes through as it grows and then divides. When this control is lost, the affected cells rapidly divide and often lose the ability to differentiate into the cell type appropriate for their location in the body. In addition, they lose contact inhibition and can start to grow on top of each other. This can result in formation of a tumor. It is important to make a distinction here: The term “cancer” is used to describe the diseases resulting from loss of cell-cycle regulation and subsequent cell proliferation. But the term “tumor” is more general. A “tumor” is an abnormal mass of cells, and a tumor can be benign (not cancerous) or malignant (cancerous).

Traditional cancer treatment uses radiation and/or chemotherapy to destroy cancer cells; however, these treatments can have unwanted side effects because they harm normal cells as well as cancer cells. Newer, promising therapies attempt to enlist the patient’s immune system to target cancer cells specifically. It is known that the immune system can recognize and destroy cancerous cells, and some researchers and immunologists also believe, based on the results of their experiments, that many cancers are eliminated by the body’s own defenses before they can become a health problem. This idea is not universally accepted by researchers, however, and needs further investigation for verification.

Cell-Mediated Response to Tumors

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor antigens. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during development; thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses against abnormal cells.

Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and differentiate into T_H1 cells. T_H1 cells release cytokines that can activate natural killer (NK) cells and enhance the killing of activated cytotoxic T cells. Both NK cells and cytotoxic T cells can recognize and target cancer cells, and induce apoptosis through the action of perforins and granzymes. In addition, activated cytotoxic T cells can bind to cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas) cytotoxic pathway.

Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death. Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers, the immune cells themselves are cancerous. In leukemia, lymphocytes that would normally facilitate the immune response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis. This may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T cells that can shut down immune responses.

The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the body’s immune defenses may someday be more successful in treating and eliminating cancer.

Check Your Understanding

Cancer Vaccines

There are two types of cancer vaccines: preventive and therapeutic. Preventive vaccines are used to prevent cancer from occurring, whereas therapeutic vaccines are used to treat patients with cancer. Most preventive cancer vaccines target viral infections that are known to lead to cancer. These include vaccines against human papillomavirus (HPV) and hepatitis B, which help prevent cervical and liver cancer, respectively.

Most therapeutic cancer vaccines are in the experimental stage. They exploit tumor-specific antigens to stimulate the immune system to selectively attack cancer cells. Specifically, they aim to enhance T_H1 function and interaction with cytotoxic T cells, which, in turn, results in more effective attack on abnormal tumor cells. In some cases, researchers have used genetic engineering to develop antitumor vaccines in an approach similar to that used for DNA vaccines (see the DNA vaccines Micro Connection in Vaccines). The vaccine contains a recombinant plasmid with genes for tumor antigens; theoretically, the tumor gene would not induce new cancer because it is not functional, but it could trick the immune system into targeting the tumor gene product as a foreign invader.

The first FDA-approved therapeutic cancer vaccine was sipuleucel-T (Provenge), approved in 2010 to treat certain cases of prostate cancer (National Institutes of Health, National Cancer Institute. “Cancer Vaccines.” Accessed on May 20, 2016.). This unconventional vaccine is custom designed using the patient’s own cells. APCs are removed from the patient and cultured with a tumor-specific molecule; the cells are then returned to the patient. This approach appears to enhance the patient’s immune response against the cancer cells. Another therapeutic cancer vaccine (talimogene laherparepvec, also called T-VEC or Imlygic) was approved by the FDA in 2015 for treatment of melanoma, a form of skin cancer. This vaccine contains a virus that is injected into tumors, where it infects and lyses the tumor cells. The virus also induces a response in lesions or tumors besides those into which the vaccine is injected, indicating that it is stimulating a more general (as opposed to local) antitumor immune response in the patient.

Check Your Understanding

Summary

• Cancer results from a loss of control of the cell cycle, resulting in uncontrolled cell proliferation and a loss of the ability to differentiate.
• Adaptive and innate immune responses are engaged by tumor antigens, self-molecules only found on abnormal cells. These adaptive responses stimulate helper T cells to activate cytotoxic T cells and NK cells of innate immunity that will seek and destroy cancer cells.
• New anticancer therapies are in development that will exploit natural adaptive immunity anticancer responses. These include external stimulation of cytotoxic T cells and therapeutic vaccines that assist or enhance the immune response.

Key terms

• tumor — collection or aggregate of cells; can be benign (noncancerous) or malignant (cancerous).

Practice

Explain how the adaptive specific immune response responds to tumors

Discuss the risks and benefits of tumor vaccines

This section is adapted from Microbiology, Section 19.5: Cancer Immunobiology and Immunotherapy by Nina Parker, Mark Schneegurt, Anh-Hue Thi Tu, Philip Lister, Brian M. Forster, and OpenStax, © OpenStax, licensed under CC BY-NC-SA 4.0. Access the original for free at openstax.org. Changes: this module’s Micro Connection (“Using Viruses to Cure Cancer”) is rendered as a callout; its source footnote (National Institutes of Health, National Cancer Institute, “Cancer Vaccines,” accessed May 20, 2016) is rendered as an inline parenthetical citation after the sentence it supports, with the bare access URL dropped; the module’s one cross-reference to another module (the DNA vaccines Micro Connection in Vaccines, Section 18.5) is rendered as an absolute site-root Markdown link, since that section is authored; the two Multiple Choice items are rendered as multiplechoice, keeping the source’s options and order; the two Fill in the Blank items are rendered as textin, keeping the source’s exact wording, with accept="preventative" added to the preventive item since the module’s own body Check Your Understanding box uses that spelling for the same concept; the source’s one unkeyed Short Answer question (“How can tumor antigens be effectively targeted without inducing an autoimmune (anti-self) response?”) stays a selfcheck, since the module states why tumor antigens CAN be targeted (they are self-antigens not screened out during lymphocyte development) but never addresses how autoimmunity specifically is avoided, so its model answer and rubric are assembled from the module’s tumor-antigen and cell-mediated-response passages and stop where the module stops; all four of the module’s body Check Your Understanding bullets stay body self-checks, since none is fixed by a single module sentence (each needs two or more sentences assembled); this module contains no <figure> and no table with a summary attribute, so no figure and no sortbins item appear on this page; three author-written filler items round the two objective groups out to this book’s floor of three items per group and eight per section, since the module’s own five exercises alone fall two short of it — one multiplechoice built from this section’s own cell-mediated-response paragraph (the CD95 (Fas) cytotoxic pathway as the “second” apoptosis-inducing mechanism cytotoxic T cells use, with distractors drawn from the same paragraph’s own terms) and two textin clozes built from this section’s own Cancer Vaccines paragraphs (hepatitis B, melanoma). No source exercise item is omitted.