Immune surveillance and protection from cancer

Cancer appears to have engaged the minds of immunologists almost since the beginning of immunology itself. Ehrlich, who opined on all things immunological, believed that the immune system could protect the host from cancer.

Burnet and Thomas refined that idea into the immune surveillance hypothesis of cancer. The hypothesis lived in limbo for several decades, failing to thrive and failing to die, until very recently when the work of Old, Schreiber, and their colleagues demonstrated that mice with a compromised immune status were more prone than immunocompetent mice to develop an array of cancers.

The immune surveillance hypothesis is often regarded as the intellectual underpinning of cancer immunology. Although the hypothesis itself has contributed little to our attempts to treat cancer through immunological means, it has profound implications for understanding the functions of the immune system.

Does infection have an anti-cancer effect?

German physicians in the 19th century noted dramatic regressions of cancer in occasional patients who developed streptococcal infections. These anecdotes led to a systematic exploration of infections/fever as an immunotherapeutic modality by William Coley, a New York City surgeon.

The work of Coley and his predecessors, suggesting that non-specific stimulation of the immune system, such as by an infection, can have an anti-cancer effect, remains a key idea in cancer immunology. It is only a small exaggeration to say that every idea in cancer immunity has been interpreted at some time or another, in terms of Coley’s observations.

Tumor immunity in the primary host

In hindsight, these successful immunizations were simply a result of allogeneic differences between tumors and the host strain of mouse, a theme that played a seminal role in definition of the MHC, but had no relevance for cancer immunity.

Q. What will happen when a tumor from a mouse of one MHC haplotype is transplanted into a recipient with a different haplotype on the first occasion or the second?

A. A transplantation rejection reaction will ensue, and these reactions display specificity and memory (see Chapter 21).

Nonetheless, amidst the barrage of experiments where MHC-mismatched tumors were transplanted into mice, were the experiments of Ludwik Gross, and later those of Prehn and Main, and of George and Eva Klein, who showed that, even when MHC-matched tumors were used to immunize mice, protection against subsequent tumor growth could be achieved (Fig. 22.1). These studies led to two principles, which have informed much of cancer immunology since and are discussed below.

Fig. 22.1 Immunogenicity of chemically induced tumors

(1) Mice immunized with tumor cells are protected against subsequent tumor growth. (2) The primary animal that develops the tumor is also immune to subsequent challenges with the same tumor.

Cancers elicit protective immunity in the primary and syngeneic host

Mice and rats of a given haplotype can be immunized with irradiated cancer cells that arose in animals of the same haplotype. When they are challenged with live cancer cells, they are able to resist the tumor challenge. The following further observations and deductions have been derived from these results.

• The immunogenicity of tumors has provided the foundation stone for the idea of tumor-specific antigens. If one could immunize, then antigens must exist.

• Tumor immunity depends on many factors. The degree of tumor immunity depends upon the type of cancer and the method of its induction, or lack of induction. UV-induced cancers are highly immunogenic, methyl-cholanthrene-induced tumors less so, and spontaneous tumors even less so. Nonetheless, immunogenicity of tumors has been demonstrated in all model systems tested.

• The primary animal develops immunity to subsequent tumor challenge. Furthermore it is also immune to subsequent challenges with the same tumor (see Fig. 22.1).

• Protective immunity is only seen in prophylactic immunization and not therapeutic immunization – once a mouse has been implanted with a tumor, immunization with irradiated cancer cells (derived from the growing tumor) does nothing to mitigate tumor growth (Fig. 22.2). Exploration of differences between prophylaxis and therapy has led to fundamental insights into tumor immunity.

Fig. 22.2 Difference between prophylaxis against future tumors and therapy of pre-existing tumors

Protective immunity is only seen in prophylactic immunization and not therapeutic immunization – once a mouse has been implanted with a tumor, immunization with irradiated cancer cells (derived from the growing tumor) does nothing to mitigate tumor growth.

It is obviously not possible to test immunogenicity of tumors in humans by the transplantation-challenge experimental paradigm. There is no other reliable method of determining immunogenicity of tumors. It is therefore impossible to comment on the immunogenicity of human tumors. Much of the work in human cancer immunity has been done with melanomas leading to suggestions that, among human tumors, melanomas are particularly immunogenic. This is an erroneous belief – melanomas are simply the easiest human tumors to culture in vitro and hence the easiest to study.

Specific immunity may develop to induced and spontaneous tumors

When mice are immunized against a given fibrosarcoma, they are rendered immune to that fibrosarcoma, but only to that individual fibrosarcoma or lines derived from it. If the mice are challenged with another fibrosarcoma, even one induced by the same carcinogen, tumor growth is unaffected by the prior immunization.

The most extensive interrogation of the individually distinct antigenicity of chemically induced tumors was carried out by Basombrio and Prehn. They induced fibrosarcomas in 25 syngeneic BALB/c mice using methyl-cholanthrene and tested the immunogenicity of each one against all other tumors in an immunization-challenge model. They concluded that, even though all tumors were induced at the same time, in the same strain of mice of the same age by the same carcinogen and were histologically all fibrosarcomas, they were antigenically individually distinct. Independent tumors induced by the same carcinogen in the same mouse are also antigenically distinct.

Q. What can you infer about the nature of the immune response to tumors from this observation?

A. It must involve the adaptive immune system.

Spontaneous tumors are also antigenically distinct

Cross-reactivity among tumors does occur occasionally. Typically, such cross-reactive immunity has been observed to be significantly weaker than the individually specific antigenicity. Efforts at characterization of such cross-reactive tumor-protective antigens have not made much headway, except in the case of virally induced tumors. In contrast, there has been considerable success in identification of individually distinct antigens.

In addition to these experimental studies, several clinical observations point to the existence of tumor-protective immunity in humans. These include the increased relative risk of cancers in patients who are immunosuppressed because they are kidney transplant recipients (Fig. 22.3) or for a variety of other reasons (Fig. 22.4).

Fig. 22.3 Relative risk of tumors in immunosuppressed kidney transplant

In all forms of immunodeficiency the relative risk of developing tumors in which viruses are known to play a role is greatly increased. This is the case for all those listed except cancer of the lung. The relative risks vary in different studies according to the duration of follow-up and the presence of co-factors such as sunlight for skin cancer.

Fig. 22.4 Tumor viruses and immunodeficiency

Skin cancer is the most common form of tumor in absolute numbers in organ transplant recipients. In other forms of immunodeficiency, tumors of the immune system dominate. Most normal adults carry both Epstein–Barr virus (EBV) and many papilloma viruses throughout life with no ill effects because they have antiviral immunity.

Q. The observation that immunosuppressed individuals are more susceptible to tumors can be explained in at least two different ways. Suggest what these explanations might be

A. The individual may be unable to control virus infections that lead to cancer (oncogenic viruses), or they may be unable to survey and control primary tumors that arise by mutation. The explanations are not mutually exclusive.

Characterization of tumor antigens

The two broad approaches to the identification of tumor antigens are shown in Figure 22.5 and discussed individually below. Not surprisingly, the approaches have yielded results that are not fully concordant. These differences have helped highlight a fascinating interplay between immunity and tolerance to tumors, discussed below.