Metastatic Melanoma in the Older Patient

Immunologic Insights and Treatment Outcomes

Upendra P Hegde; Nitya Chakraborty; Bijay Mukherji; Jane M Grant Kels


Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(2):185-193. 

In This Article

Imbalances Rather than Just Weakness in the Aging Immune System

Although the different components of the immune system in the elderly that function to maintain immune homeostasis become weaker with age, close examination of the aging immune system has led to the discovery of a number of imbalances rather than generalized weaknesses.

First, the decreased output of naive T lymphocytes from the aged primary immune organs (i.e., bone marrow and thymus) become even lower in the setting of increased cumulative infections and lead to an increase in memory cells and an exhaustive phenotype.[38] The reversal ratio of naive to memory phenotype of the lymphocytes highlights this inference. Second, the aging-associated changes in the lipid membrane of the effector T lymphocytes of the older patient are believed to result in weakened effector T-lymphocyte responses when exposed to antigens. Their regulation by aging Tregs will finally determine effective anti-tumor T-lymphocyte responses. This area of research seems to provide conflicting data, although the majority of the studies seem to support weaker anti-tumor responses in the setting of enhanced Treg activity.[39,40] Third, the underlying proinflammatory cytokines resulting from chronic antigenic stimulation of the older patient's innate immune system is believed to lead to an inflammatory state. Our in vitro data suggest that the anti-melanoma effector T-cell responses were more skewed towards a favorable Th1- rather than Th2-type response, which might explain improved anti-melanoma immunity in vivo in some elderly patients.[41]

Therefore, we believe that aging-associated changes of the immune system and its impact on patients with MM should be viewed in the context of imbalances in the immune system rather than the perceived progressive weakening of the immune system. Therefore, it is possible that the actual impact of an imbalanced immune system on anti-melanoma immunity favors anti-tumor activity rather than being a barrier to anti-tumor immunity. We propose that aging-associated imbalances between a relatively weakened regulatory apparatus and functionally active effector activity of the adaptive immune system would generate clinically relevant anti-tumor immunity in response to the presentation by the APCs of either spontaneously shed tumor epitopes or those generated by the use of chemotherapeutic agents in elderly patients. The predominantly inflammatory cytokines that accompany the aging physiology could polarize the anti-tumor immune responses towards anti-tumor Th1 responses and, along with a relatively weaker Treg activity, could lead to favorable anti-melanoma response at the tumor site, resulting into an indolent clinical course and often dramatic tumor responses to systemic chemotherapy, as seen in some older patients with MM. This is in stark contrast to a usually very aggressive clinical course we see in younger patients with MM where effector immune responses are probably highly regulated, while the anti-inflammatory cytokines are inhibitory to the effective anti-tumor immune responses (Figure 1). Future work in this field will also need to include a deeper understanding of (melanoma) tumor cell biology that emphasizes growth kinetics and sensitivities to chemotherapeutic agents in the older patient population.

Figure 1.

Proposed hypothesis describing slow growth or chemotherapy-responsive melanoma metastasis in some elderly patients treated with chemotherapeutic agents owing to an age-associated imbalance of immune system and secreted cytokines. Immune homeostasis is maintained by a delicate balance between the anti-tumor immune response (CD8+ T lymphocytes), its regulation (Tregs) and the cytokine milieu in the tumor (proinflammatory cytokines vs anti-inflammatory cytokines). Increased Treg activity in the presence of anti-inflammatory cytokines causes tumor resistance while decreased Treg activity in the presence of proinflammatory cytokines results in tumor cell death. The effect is amplified when tumor antigens are generated by chemotherapy-induced tumor cell death.
Multiple '+' signs denote stronger activity of Tregs, while multiple '-' signs represent decreased activity of regulation.
APC: Antigen-presenting cell.


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