Wednesday, July 6, 2016
??? reason for latency....time between attacks....in some melanoma patients
Melanoma lesions independently acquire T-cell resistance during metastatic latency. Zhao, Sucker, Horn, et al. Cancer Res. 2016 Jun 3.
Melanoma often recurs after a latency period of several years, presenting a T cell-edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen-specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell-resistant, HLA class I-negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance towards dominant CD8+ T cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Junhigh/MITFlow phenotype, possibly associated with immunosuppression, which contrasted with a c-Junlow/MITFhigh phenotype of T cell-edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance.
Basically, this is saying that when these researchers looked at different mets, they found that the individual tumors became resistant by modifying their surface molecule presentation making attack by the existing t-cells ineffective. How? Why? Research like this is coming closer to answers we need in order to figure out what can be done to PREVENT the development of resistance!!!
I was lucky enough to go almost five years between my first cutaneous melanoma (with a positive node - 2003 to late 2007) with no treatment other than surgical excision of the area and nodal basin, as there was none other than interferon. But in 2007, I was dealing with another cutaneous lesion, no positive nodes. After another resection of the lesion and that nodal basin - I developed brain and lung mets three years later in 2010. I have some dear ones who went 7, 10, 15, 17 YEARS between initial lesions and subsequent development of Stage IV melanoma. What EXACTLY protected us? What PRECISELY caused the ultimate failure of our immune systems? These are answers we need to find!!! I have pondered and researched this before. I published this in 2012: What I've been saying about 'indolent melanoma'!
While some of us get lucky with relatively indolent disease, and treatments have improved, too many precious peeps are diagnosed at Stage III or IV and are gone within a couple years, often after trying every treatment out there. THIS IS NOT OK! I guess I'll stop and try to settle down...for now. love, c